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1.  Expression and Regulation of the PD-L1 Immunoinhibitory Molecule on Microvascular Endothelial Cells 
Objective
To evaluate the expression and regulation of a novel B7-like protein, PD-L1, the ligand for the immunoinhibitory receptor PD-1 expressed on activated T-cells, on microvascular endothelial cells (ECs)
Methods
PD-L1 expression on ECs in vitro and in vivo was quantified by using a dual radiolabeled antibody technique after treatment with interferons (IFN) and IL-12, respectively. Changes in the level of PD-L1 mRNA were determined by using RT-PCR.
Results
PD-L1 was observed to be present on ECs under basal conditions. Treatment of ECs with IFN-α, -β and -γ, but not LPS, was observed to induce elevations in the mRNA and surface expression of PD-L1 on ECs. By using a dual radiolabeled monoclonal antibody (mAb) technique, PD-L1 expression in various tissues of control and IL-12 challenged wild-type and IFN-γ-deficient mice was measured. A significant increase in PD-L1 expression was observed in tissues at 24 hours after IL-12-challenge, with peak levels of PD-L1 occurring 72 hours after IL-12 challenge. IL-12 was not effective at inducing PD-L1 expression in tissues of IFN-γ-deficient mice.
Conclusions
These data show the expression of a novel B7-like molecule on murine ECs that is mediated by IFN-α, -β, and -γ, and suggest a potential pathway by which ECs may modulate T-cell function.
doi:10.1038/sj/mn/7800123
PMCID: PMC3740166  PMID: 11932780
endothelial cell; costimulation; T-lymphocyte; cellular activation
2.  Stromal endothelial cells establish a bidirectional crosstalk with chronic lymphocytic leukemia cells through the TNF-related factors BAFF, APRIL and CD40L 
Chronic lymphocytic leukemia (CLL) is a clonal B cell disorder of unknown origin. Accessory signals from the microenvironment are critical for the survival, expansion and progression of malignant B cells. We found that the CLL stroma included microvascular endothelial cells (MVECs) expressing BAFF and APRIL, two TNF family members related to the T cell-associated B cell-stimulating molecule CD40 ligand (CD40L). Constitutive release of soluble BAFF and APRIL increased upon engagement of CD40 on MVECs by CD40L aberrantly expressed on CLL cells. In addition to enhancing MVEC expression of the CD40 receptor, leukemic CD40L induced cleavases that elicited intracellular processing of pro-BAFF and pro-APRIL proteins in MVECs. The resulting soluble BAFF and APRIL proteins delivered survival, proliferation, Ig gene-remodeling and differentiation signals by activating CLL cells through TACI, BAFF-R and BCMA receptors. BAFF and APRIL further amplified CLL cell survival by up-regulating the expression of leukemic CD40L. Inhibition of TACI, BCMA and BAFF-R expression on CLL cells, abrogation of CD40 expression in MVECs, or suppression of BAFF and APRIL cleavases in MVECs reduced the survival and diversification of malignant B cells. These data indicate that BAFF, APRIL and CD40L form a CLL-enhancing bidirectional signaling network linking neoplastic B cells with the microvascular stroma.
doi:10.4049/jimmunol.1102066
PMCID: PMC3370079  PMID: 22593611
Human; B cells; Antibodies; Cell Activation; Neoplasia
4.  Induction of prolonged early G1 arrest by CDK4/CDK6 inhibition reprograms lymphoma cells for durable PI3Kδ inhibition through PIK3IP1 
Cell Cycle  2013;12(12):1892-1900.
Phosphatidylinositol-3-kinase (PI3K) signaling is constitutive in most human cancers. Selective inhibition of PI3Kδ (p110δ) by GS-1101 has emerged as a promising therapy in chronic lymphocytic leukemia and indolent lymphomas. In aggressive non-Hodgkin lymphomas such as mantle cell lymphoma (MCL), however, efficacy has been observed, but the extent and duration of tumor control is modest. To determine if tumor killing by GS-1101 is cell cycle-dependent, we show in primary MCL cells by whole-transcriptome sequencing that, despite aberrant expression and recurrent mutations in Cyclin D1, mutations are rare in coding regions of CDK4, RB1 and other genes that control G1-S cell cycle progression or PI3K/AKT signaling. PI3Kδ is the predominant PI3K catalytic subunit expressed, and inhibition by GS-1101 transiently inhibits AKT phosphorylation but not proliferation in MCL cells. Induction of prolonged early G1-arrest (pG1) by selective inhibition of CDK4/CDK6 with PD 0332991 amplifies and sustains PI3Kδ inhibition, which leads to robust apoptosis. Accordingly, inhibition of PI3Kδ induces apoptosis of primary MCL tumor cells once they have ceased to cycle ex vivo, and this killing is enhanced by PD 0332991 inhibition of CDK4/CDK6. PIK3IP1, a negative PI3K regulator, appears to mediate pG1 sensitization to PI3K inhibition; it is markedly reduced in MCL tumor cells compared with normal peripheral B cells, profoundly induced in pG1 and required for pG1 sensitization to GS-1101. Thus, the magnitude and duration of PI3K inhibition and tumor killing by GS-1101 is pG1-dependent, suggesting induction of pG1 by CDK4/CDK6 inhibition as a strategy to sensitize proliferating lymphoma cells to PI3K inhibition.
doi:10.4161/cc.24928
PMCID: PMC3735703  PMID: 23676220
CDK4; CDK6; GS-1101; PD 0332991; PI3Kα; PI3Kδ; PIK3IP1; mantle cell lymphoma
5.  Stem Cell Mobilization with Cyclophosphamide Overcomes the Suppressive Effect of Lenalidomide Therapy on Stem Cell Collection in Multiple Myeloma 
A total of 28 treatment-naïve patients with stage II or III multiple myeloma (MM) were treated with the combination of clarithromycin, lenalidomide, and dexamethasone (BiRD). Stem cells were collected following granulocyte- colony stimulating factor (G-CSF) or cyclophosphamide (Cy) plus G-CSF mobilization at maximum response. Sufficient stem cells for 2 autologous stem cell transplants were collected from all patients mobilized with Cy plus G-CSF, versus 33% mobilized with G-CSF alone (P<.0001). The duration of prior lenalidomide therapy did not correlate with success of stem cell harvests (P = .91). In conclusion, Cy can be added to G-CSF for stem cell mobilization to successfully overcome the suppressive effect of prior treatment with lenalidomide.
doi:10.1016/j.bbmt.2008.04.008
PMCID: PMC3626097  PMID: 18541199
Autologous stem cell transplantation; Cyclophosphamide; Lenalidomide; Multiple myeloma; Stem cell mobilization
6.  Atypical serum immunofixation patterns frequently emerge in immunomodulatory therapy and are associated with a high degree of response in multiple myeloma 
British journal of haematology  2008;143(5):654-660.
Summary
The M-protein is the major reference measure for response in multiple myeloma (MM) and its correct interpretation is key to clinical management. The emergence of oligoclonal banding is recognized as a benign finding in the post-autologous stem cell transplantation setting (ASCT) for MM but its significance during non-myeloablative therapy is unknown. In a study of the immunomodulatory combination BiRD, (lenalidomide and dexamethasone with clarithromycin), we frequently detected the emergence of mono- and oligo-clonal immunoglobulins unrelated to the baseline diagnostic M-protein. The new M-proteins seen on serum immunofixation electrophoresis were clearly different in either heavy or light chain component(s) from the original M-spike protein and were called atypical serum immunofixation patterns (ASIPs). Overall, 24/72 (33%) patients treated with BiRD developed ASIPs. Patients who developed ASIPs compared with patients treated with BiRD without ASIPs, had a significantly greater overall response (100% vs. 85%) and complete response rates (71% vs. 23%). ASIPs were not associated with new clonal plasma cells or other lymphoproliferative processes, and molecular remissions were documented. This is the first time this phenomenon has been seen with regularity in non-myeloablative therapy for MM. Analogous to the ASCT experience, ASIPs do not signal incipient disease progression, but rather herald robust response.
doi:10.1111/j.1365-2141.2008.07374.x
PMCID: PMC3626496  PMID: 18950461
lenalidomide; multiple myeloma; atypical serum immunofixation patterns; M-protein
7.  Loss of GM3 synthase gene, but not sphingosine kinase 1, is protective against murine nephronophthisis-related polycystic kidney disease 
Human Molecular Genetics  2012;21(15):3397-3407.
Genetic forms of polycystic kidney diseases (PKDs), including nephronophthisis, are characterized by formation of fluid-filled cysts in the kidneys and progression to end-stage renal disease. No therapies are currently available to treat cystic diseases, making it imperative to dissect molecular mechanisms in search of therapeutic targets. Accumulating evidence suggests a pathogenic role for glucosylceramide (GlcCer) in multiple forms of PKD. It is not known, however, whether other structural glycosphingolipids (GSLs) or bioactive signaling sphingolipids (SLs) modulate cystogenesis. Therefore, we set out to address the role of a specific GSL (ganglioside GM3) and signaling SL (sphingosine-1-phosphate, S1P) in PKD progression, using the jck mouse model of nephronopthisis. To define the role of GM3 accumulation in cystogenesis, we crossed jck mice with mice carrying a targeted mutation in the GM3 synthase (St3gal5) gene. GM3-deficient jck mice displayed milder PKD, revealing a pivotal role for ganglioside GM3. Mechanistic changes in regulation of the cell-cycle machinery and Akt-mTOR signaling were consistent with reduced cystogenesis. Dramatic overexpression of sphingosine kinase 1 (Sphk1) mRNA in jck kidneys suggested a pathogenic role for S1P. Surprisingly, genetic loss of Sphk1 exacerbated cystogenesis and was associated with increased levels of GlcCer and GM3. On the other hand, increasing S1P accumulation through pharmacologic inhibition of S1P lyase had no effect on the progression of cystogenesis or kidney GSL levels. Together, these data suggest that genes involved in the SL metabolism may be modifiers of cystogenesis, and suggest GM3 synthase as a new anti-cystic therapeutic target.
doi:10.1093/hmg/dds172
PMCID: PMC3392114  PMID: 22563011
8.  Safety, Pharmacokinetics, Pharmacodynamics, and Activity of Navitoclax, a Targeted High Affinity Inhibitor of BCL-2, in Lymphoid Malignancies 
The lancet oncology  2010;11(12):1149-1159.
SUMMARY
Background
BCL-2 family proteins play a central role in regulating clonal selection and survival of lymphocytes and are frequently over expressed in lymphomas. Navitoclax (ABT-263) is a targeted high-affinity small molecule that occupies the BH3 binding groove of BCL-2 and BCL-XL and inhibits their anti-apoptotic activity. Experimentally, navitoclax kills cells in a BAX/BAK-dependent manner and results in regression of lymphoid tumors in xenograft models.
Methods
This is a phase I dose-escalation study of navitoclax in patients with relapsed or refractory lymphoid malignancies. Study endpoints included safety, maximum tolerated dose (MTD), pharmacokinetic profile and clinical activity. In addition, mechanism-based pharmacodynamic effects on platelets and lymphocytes were assessed. Navitoclax was orally administered and assessed on an intermittent schedule of once daily for 14 days followed by 7 days off (14/21 days) or on a continuous once daily schedule (21/21 days). This trial is registered with ClinicalTrials.gov, number NCT00406809.
Findings
Fifty-five patients were enrolled, (median age 59 years, IQR 51–67), of whom two did not complete the first cycle and were not evaluable for assessment of dose-limiting toxicity (DLT). Common toxicities included grade 1/2 diarrhea and fatigue in 31 and 21 patients, respectively. Thrombocytopenia and neutropenia were the serious common toxicities with grade 3/4 observed in 29 and 17 patients, respectively. On the intermittent schedule (14/21), 5 DLT’s were observed; two due to hospitalizations for bronchitis and pleural effusion, and one each due to grade 3 transaminase elevation, grade 4 thrombocytopenia and grade 3 cardiac arrhythmia. Navitoclax caused a rapid and dose-dependent decline in peripheral platelets following initial drug exposure, followed by a rebound. To reduce the platelet nadir associated with intermittent dosing, a lead-in dose followed by continuous dosing (21/21 schedule) was examined. Three DLT’s were observed on this schedule (21/21); one each due to grade 4 thrombocytopenia, grade 3 transaminase elevation and grade 3 gastrointestinal bleed. Navitoclax showed a pharmacodynamic effect on circulating platelets and T-cells. Based on these findings, a 150 mg 7-day lead-in dose followed by 325 mg dose administered on a continuous (21/21) schedule was selected for phase II study. Clinical responses occurred at all dose levels and in multiple histologies. Partial responses were observed in 10 of 46 patients with evaluable disease, and the responders had a median progression-free survival of 455 days (IQR 40-218).
doi:10.1016/S1470-2045(10)70261-8
PMCID: PMC3025495  PMID: 21094089
9.  Pilot Study of Aurora, a Social, Mobile-Phone-Based Emotion Sharing and Recording System 
Background:
Emotion is a ubiquitous aspect of humanity that governs behavior in a number of ways and is linked inextricably with health. Pausing to evaluate one’s emotional state in the face of decisions and reflecting on past patterns of emotion have been shown to improve behaviors. Further, social expression of emotion has been shown to directly improve health outcomes. While the virtual reality research community does not ignore emotion on the whole, there does exist a need to explore what roles emotional awareness and emotion sharing can play in this domain.
Methods:
A mobile-phone-based social emotion recording and sharing system, Aurora, was developed to provide individuals with a means to pause and evaluate their emotional state, reflect on past emotions, share emotions with others, and participate in socially supportive activities with peers. A study was conducted with 65 subjects to evaluate Aurora as a tool to encourage emotional reflection and awareness as well as social sharing of emotion.
Results:
Users of Aurora reported an increased comfort in socially expressing emotion and were encouraged to share emotions, even with strangers. Subjects also reported liking reflecting on their emotional state and found it valuable. Subjects’ behavior also suggested that the system encouraged individuals to reach out to one another in acts of social support.
Conclusions:
The Aurora system offers a tool for encouraging emotional awareness, emotion sharing, and socially supportive behavior. Such a tool could be impactful in numerous health settings where emotion is considered to be an important indicator of or influence on outcome, such as for weight loss, alcohol cessation, or cancer sufferers.
PMCID: PMC3125924  PMID: 21527101
emotion; mobile; social support
10.  Radioimmunotherapy with tositumomab and iodine-131 tositumomab for non-Hodgkin’s lymphoma 
Biologics : Targets & Therapy  2007;1(2):113-120.
With the success of targeted monoclonal antibody therapy in non-Hodgkin’s lymphoma, attempts were made to further improve efficacy through the addition of a radioisotope. A goal of radioimmunotherapy is to utilize the monoclonal antibody to deliver radiation to a tumor bed with relatively limited toxicity to the surrounding normal tissues. I-131 Tositumomab is an iodine-131 labeled anti-CD20 murine IgG2a monoclonal antibody and is one of two FDA-approved radioimmunotherapeutic drugs for patients with non-Hodgkin’s lymphoma (NHL). For more than a decade now, radiolabeled tositumomab has principally been evaluated in low-grade and transformed low-grade NHL patients with proven efficacy in both the up-front and salvage settings. Studies have included its use as a single agent, in combination with chemotherapy and as part of a conditioning regimen for autologous stem cell transplantation. These data suggest that this agent has an important role in the treatment of patients with B cell lymphoma.
PMCID: PMC2721297  PMID: 19707321
non-Hodgkin’s lymphoma; tositumomab; iodine-131-labeled tositumomab; B-cell lymphoma
11.  Durable Responses with the Metronomic Regimen RT-PEPC in Elderly Patients with Recurrent Mantle Cell Lymphoma 
Cancer  2010;116(11):2655-2664.
BACKGROUND
Targeting the tumor microenvironment and angiogenesis is a novel lymphoma therapeutic strategy. We report safety, activity and angiogenic profiling with the RT-PEPC regimen (rituximab with thalidomide, and prednisone, etoposide, procarbazine and cyclophosphamide) in recurrent mantle cell lymphoma (MCL).
METHODS
RT-PEPC includes induction (months 1–3) of weekly rituximab × 4, daily thalidomide (50 mg) and PEPC, then maintenance thalidomide (100 mg), oral PEPC titrated to neutrophil count, and rituximab every 4 months. Endpoints included safety, efficacy, quality of life (QoL), and translational studies including tumor angiogenic phenotyping, plasma VEGF and circulating endothelial cells.
RESULTS
Twenty-five pts were enrolled (22 evaluable) with median age 68 yrs (range 52–81), 24 (96%) stage III/IV, 18 (72%) IPI 3–5, 20 (80%) high risk MIPI, median 2 prior therapies (range 1–7), and 15 (60%) bortezomib progressors. At a median follow-up of 38 months, ORR was 73% (32% CR/CRu, 41% PR, n=22) and median PFS 10 months. Four CRs are ongoing (6+, 31+, 48+ and 50+ months). Toxicities included grade 1–2 fatigue, rash, neuropathy and cytopenias including grade 1–2 thrombocytopenia (64%) and grade 3–4 neutropenia (64%). Two thromboses and 5 grade 3–4 infections occurred. QoL was maintained or improved. Correlative studies demonstrated tumor autocrine angiogenic loop (expression of VEGFA and VEGFR1) and heightened angiogenesis and lymphangiogenesis in stroma. Plasma VEGF and circulating endothelial cells trended down with treatment.
CONCLUSIONS
RT-PEPC has significant and durable activity in MCL, with manageable toxicity and maintained QoL. Novel low-intensity approaches warrant further evaluation, potentially as initial therapy in elderly patients.
doi:10.1002/cncr.25055
PMCID: PMC3004744  PMID: 20235190
12.  Phase II Multi-Institutional Trial of the Histone Deacetylase Inhibitor Romidepsin As Monotherapy for Patients With Cutaneous T-Cell Lymphoma 
Journal of Clinical Oncology  2009;27(32):5410-5417.
Purpose
Romidepsin (depsipeptide or FK228) is a member of a new class of antineoplastic agents active in T-cell lymphoma, the histone deacetylase inhibitors. On the basis of observed responses in a phase I trial, a phase II trial of romidepsin in patients with T-cell lymphoma was initiated.
Patients and Methods
The initial cohort was limited to patients with cutaneous T-cell lymphoma (CTCL), or subtypes mycosis fungoides or Sézary syndrome, who had received no more than two prior cytotoxic regimens. There were no limits on other types of therapy. Subsequently, the protocol was expanded to enroll patients who had received more than two prior cytotoxic regimens.
Results
Twenty-seven patients were enrolled onto the first cohort, and a total of 71 patients are included in this analysis. These patients had undergone a median of four prior treatments, and 62 patients (87%) had advanced-stage disease (stage IIB, n = 15; stage III, n= 6; or stage IV, n = 41). Toxicities included nausea, vomiting, fatigue, and transient thrombocytopenia and granulocytopenia. Pharmacokinetics were evaluated with the first administration of romidepsin. Complete responses were observed in four patients, and partial responses were observed in 20 patients for an overall response rate of 34% (95% CI, 23% to 46%). The median duration of response was 13.7 months.
Conclusion
The histone deacetylase inhibitor romidepsin has single-agent clinical activity with significant and durable responses in patients with CTCL.
doi:10.1200/JCO.2008.21.6150
PMCID: PMC2773225  PMID: 19826128
13.  Bendamustine Is Effective Therapy in Patients With Rituximab-Refractory, Indolent B-cell Non-Hodgkin Lymphoma 
Cancer  2010;116(1):106-114.
Background
Bendamustine hydrochloride is a novel alkylating agent. In this multicenter study, the authors evaluated the efficacy and toxicity of single-agent bendamustine in patients with rituximab-refractory, indolent B-cell lymphoma.
Methods
Eligible patients (N = 100, ages 31-84 years) received bendamustine at a dose of 120 mg/m2 by intravenous infusion on Days 1 and 2 every 21 days for 6 to 8 cycles. Histologies included follicular (62%), small lymphocytic (21%), and marginal zone (16%) lymphomas. Patients had received a median of 2 previous regimens (range, 0-6 previous regimens), and 36%were refractory to their most recent chemotherapy regimen. Primary endpoints included overall response rate (ORR) and duration of response (DOR). Secondary endpoints were safety and progression-free survival (PFS).
Results
An ORR of 75% (a 14% complete response rate, a 3% unconfirmed complete response rate, and a 58% partial response rate) was observed. The median DOR was 9.2 months, and median PFS was 9.3 months. Six deaths were considered to be possibly treatment related. Grade 3 or 4 (determined using National Cancer Institute Common Toxicity Criteria [version 3.0.19]. reversible hematologic toxicities included neutropenia (61%), thrombocytopenia (25%), and anemia (10%). The most frequent nonhematologic adverse events (any grade) included nausea (77%), infection (69%), fatigue (64%), diarrhea (42%), vomiting (40%), pyrexia (36%), constipation (31%), and anorexia (24%).
Conclusions
Single-agent bendamustine produced a high rate of objective responses with acceptable toxicity in patients with recurrent, rituximab-refractory indolent B-cell lymphoma.
doi:10.1002/cncr.24714
PMCID: PMC2916680  PMID: 19890959
bendamustine; non-Hodgkin lymphoma; B-cell lymphoma; rituximab-refractory; clinical trial
14.  Targeting angiogenesis: A novel, rational therapeutic approach for Non-Hodgkin’s Lymphoma 
Leukemia & lymphoma  2009;50(5):679.
doi:10.1080/10428190902893835
PMCID: PMC2819380  PMID: 19452312
15.  Cytosolic phospholipase A2α–deficient mice are resistant to experimental autoimmune encephalomyelitis 
Experimental autoimmune encephalomyelitis (EAE), a Th1-mediated inflammatory disease of the central nervous system (CNS), is a model of human multiple sclerosis. Cytosolic phospholipase A2α (cPLA2α), which initiates production of prostaglandins, leukotrienes, and platelet-activating factor, is present in EAE lesions. Using myelin oligodendrocyte glycoprotein (MOG) immunization, as well as an adoptive transfer model, we showed that cPLA2α−/− mice are resistant to EAE. Histologic examination of the CNS from MOG-immunized mice revealed extensive inflammatory lesions in the cPLA2α+/− mice, whereas the lesions in cPLA2α−/− mice were reduced greatly or completely absent. MOG-specific T cells generated from WT mice induced less severe EAE in cPLA2α−/− mice compared with cPLA2α+/− mice, which indicates that cPLA2α plays a role in the effector phase of EAE. Additionally, MOG-specific T cells from cPLA2α−/− mice, transferred into WT mice, induced EAE with delayed onset and lower severity compared with EAE that was induced by control cells; this indicates that cPLA2α also plays a role in the induction phase of EAE. MOG-specific T cells from cPLA2α−/− mice were deficient in production of Th1-type cytokines. Consistent with this deficiency, in vivo administration of IL-12 rendered cPLA2α−/− mice susceptible to EAE. Our data indicate that cPLA2α plays an important role in EAE development and facilitates differentiation of T cells toward the Th1 phenotype.
doi:10.1084/jem.20050665
PMCID: PMC2212947  PMID: 16172261

Results 1-15 (15)