Cancer Research Institute

About: Cancer Research Institute is a nonprofit organization based out in New York, New York, United States. It is known for research contribution in the topics: Cancer & Population. The organization has 1061 authors who have published 754 publications receiving 26712 citations.

Transcriptome Signature of Vγ9Vδ2 T Cells Treated With Phosphoantigens and Notch Inhibitor Reveals Interplay Between TCR and Notch Signaling Pathways.

Abstract: Gamma delta (γδ) T cells, especially the Vγ9Vδ2 subtype, have been implicated in cancer therapy and thus have earned the spotlight in the past decade. Although one of the most important properties of γδ T cells is their activation by phosphoantigens, which are intermediates of the Mevalonate and Rohmer pathway of isoprenoid biosynthesis, such as IPP and HDMAPP, respectively, the global effects of such treatments on Vγ9Vδ2 T cells remain elusive. Here, we used the high-throughput transcriptomics approach to elucidate the transcriptional changes in human Vγ9Vδ2 T cells upon HDMAPP, IPP, and anti-CD3 treatments in combination with interleukin 2 (IL2) cytokine stimulation. These activation treatments exhibited a dramatic surge in transcription with distinctly enriched pathways. We further assessed the transcriptional dynamics upon inhibition of Notch signaling coupled with activation treatments. We observed that the metabolic processes are most affected upon Notch inhibition via GSI-X. The key effector genes involved in gamma-delta cytotoxic function were downregulated upon Notch blockade even in combination with activation treatment, suggesting a transcriptional crosstalk between T-cell receptor (TCR) signaling and Notch signaling in Vγ9Vδ2 T cells. Collectively, we demonstrate the effect of the activation of TCR signaling by phosphoantigens or anti-CD3 on the transcriptional status of Vγ9Vδ2 T cells along with IL2 stimulation. We further show that the blockade of Notch signaling antagonistically affects this activation.

Prevalence and analysis of tobacco use disorder in patients diagnosed with lung cancer.

Abstract: Introduction Tobacco use disorder (TUD), previously known as nicotine dependence, was associated with increased risk of lung cancer. However, little is known about the prevalence of TUD and symptom manifestation in smokers with lung cancer. Objectives The aim of the present study was to investigate the prevalence of TUD using DSM-5 diagnostic criteria in patients diagnosed with lung cancer and analyze their tobacco use characteristics. Methods A total of 200 histologically confirmed lung cancer patients who used tobacco within the prior 12-month period at the time of diagnosis were recruited for this study. Participants were assessed using interviewer-administered questionnaires to determine TUD symptoms and smoking-related behaviors, and self-administered Fagerstrom Test for Nicotine Dependence (FTND) was also administered. Results The prevalence of DSM-5 TUD was 92.0% (n = 184). Of a total of 200 subjects, 23 (11.5%), 35 (17.5%), and 126 (63.0%) were classified into mild, moderate, and severe TUD categories, respectively. A total of 19 (81.3%) moderate TUD and 98 (77.8%) severe TUD patients had attempted smoking cessation. Of these subjects, 21 (21.4%) severe TUD and 12 (63.2%) moderate TUD patients tried more than three times. The number of satisfied criteria under DSM-5 TUD was positively correlated with FTND score, cumulative lifetime smoking amount, and daily smoking levels. Conclusions Smokers diagnosed with lung cancer showed a high prevalence of DSM-5 TUD. Their heavy and consistent tobacco use suggests reduced motivation to abstain from smoking.

Hairy cell leukemia: early immunophenotypical detection and quantitative analysis by flow cytometry.

Abstract: UNLABELLED The abnormal coexpression of the so-called 'HCL-restricted' markers (CD22+CD11c, CD25 and CD103) identified on monotypic, slightly large B-lymphocytes in the large cell-gate of dot-plots has previously been shown to be highly characteristic of hairy cell leukemia (HCL). The main aim of our present study was to determine if patterns with low levels of neoplastic cells in bone marrow (BM) or peripheral blood (PB) are of a value the early diagnosis and/or detection of minimal residual disease (MRD) in HCL. Next we wished to determine if quantitative immunophenotyping given by molecules of equivalent soluble fluoresceine (MESF) could help to distinguish pathologic B-lymphocytic pool from that of normal residual B-cells also in patients with low numbers of HCL cells. The abnormal immunophenotypes were studied in 174 specimens from 19 patients with suspect HCL or during follow-up of already treated patients. For evaluation of marker density fluorescent calibration microbeads were used. In 12 HCL patients (67%) permanent complete remission was observed after treatment. In 6 patients (33%) transient MRD+ phenotype was identified but the clinical manifestation of relapse was followed till now in only three patients. One patient was phenotyped just only at diagnosis. The pathological cells in low levels were found in 5 patients at diagnosis (in the range from 2 to 12%) and in patients with MRD+ phenotype they were recognized repeatedly in the range from 2 to 8%. Furthermore, we observed in hairy cells significantly higher values of molecule numbers of some B-cell markers, comparing to that of residual B-cells in nonleukemic lymphocyte gate of the same sample. We found profound and persistent CD4+ lymphopenia in all but one studied patients after CdA treatment. CONCLUSIONS Flow cytometric immunophenotyping of PB and BM is highly sensitive and specific method and is capable to detect low levels of malignant cells in HCL. Quantitative analysis of MESF values of pathological B-cells comparing to normal residual B-cells seems to be another new marker of HCL in common, which is reliable detecting also small cell numbers in examined sample. A long-term decline of CD4+ T-cells correlated with the relatively low incidence of clinical progression of HCL.

Genetic ablation of pregnancy zone protein promotes breast cancer progression by activating TGF-β/SMAD signaling

Abstract: Pregnancy zone protein (PZP) is best known as protease inhibitor and its concentration in human blood plasma increases dramatically during pregnancy. Recent investigation revealed a role of PZP inactivating germ-line mutation in breast cancer predisposition, and therefore we designed a study to evaluate functional involvement of this protein in tumor pathogenesis. PZP knockout cells were generated utilizing the CRISPR-Cas9 approach in MCF7 and T47D (breast cancer) cell lines, and colony formation, cell proliferation, and migration assays carried out. TGF-β and SMAD expression studies were performed using qRT-PCR and Western blot. PZP expression in tumor vs normal tissue was compared using meta-analyses of data records of breast cancer patients (n = 1211) included in the TCGA consortium registry as well as in independent cohorts of hormone receptor-positive (n = 118) and triple-negative breast cancer (TNBC) patients (n = 116). We demonstrated that genetic ablation of PZP efficiently inhibits tamoxifen-induced apoptosis and enhances cell proliferation, migration, and colony-forming capacity. We found a significant increase in survival fraction of CRISPR/Cas9-mediated PZP knockout clones compared to wild-type counterpart after tamoxifen treatment (p < 0.05). The PZP knockout significantly promoted breast cancer cell migration (p < 0.01) in vitro. We observed high expression of TGF-β2 ligand, TGF-β- receptor 2, and upregulation of phosphorylated regulatory-SMADs (pSMAD2 and pSMAD3) activating the pro-survival function of TGF-β/SMAD signaling in PZP knockout clones. Meta-analyses of data records of breast cancer patients indicated that low PZP expression is associated with poor overall survival at 6 years (51.7% vs 62.9% in low vs high expressers, respectively; p = 0.026). We also observed a significantly lower PZP mRNA expression in TNBC as compared with hormone receptor-positive tumors (p = 0.019). Taken together, our results suggest that genetic ablation of PZP results in tumor progression and low expression of PZP is associated with poor survival of breast cancer patients.

14-3-3 proteins mediate the localization of Centrin2 to centrosome.

Abstract: 14-3-3e and 14-3-3γ localize to the centrosome and regulate centrosome duplication, by inhibiting cdc25C function. As 14-3-3γ and 14-3-3e form a complex with centrosomal proteins, we asked if this ability was required to regulate centrosome duplication. The results in this report demonstrate that 14-3-3e and 14-3-3γ form a complex with Centrin2 and that the binding site is located in the N-terminal EF hand in Centrin2, EF1. A Centrin2 mutant that does not form a complex with 14-3-3 proteins displays a punctate cytoplasmic localization and does not localize to the centrosome. These results suggest that in addition to negatively regulating centrosome duplication as previously reported, 14-3-3 proteins might also be required for centriole biogenesis by regulating the localization of Centrin2 at the centrosome.