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Eslamian L.,Shahid Beheshti University of Medical Sciences | Borzabadi-Farahani A.,University of Warwick | Borzabadi-Farahani A.,Childrens Hospital Los Angeles CHLA | Borzabadi-Farahani A.,University of Southern California | And 3 more authors.
Lasers in Medical Science | Year: 2014

The purpose of this study was to assess the effect of 810-nm (DMC Equipamentos, Sao Carlos, Brazil) continuous wave low-level laser therapy (LLLT) on the pain caused by orthodontic elastomeric separators. Thirty-seven orthodontic patients (12 male and 25 female, aged 11-32 years, mean age = 24.97 years) participated in the study, including 20 subjects aged 18 years or more, and 17 under 18 years of age. Four elastomeric separators (Dentarum, Springen, Germany) were placed for the first permanent molars (distal and mesial), either for maxillary (22 patients) or mandibular (15 patients) arches; one quadrant was randomly selected and used as a placebo group (received no laser irradiation). After separator placement for each quadrant, patients received 10 doses (2 J/cm2, 100 mW, 20 s) of laser irradiation on the buccal side (at the cervical third of the roots), for distal and mesial of the second premolars and first permanent molars, as well as distal of second permanent molars (five doses). The same procedure was repeated for the lingual or palatal side (five doses). After 24 h, patients returned to the clinic and received another 10 doses of laser irradiation on the same quadrant. Postseparation pain level recorded on a 10-cm visual analog scale for both jaws immediately (hour 0), and after 6, 24, 30 h, as well as on days 3, 4, 5, 6, and 7. Significant differences in the pain perception (PP) were found between the laser and placebo groups at 6, 24, 30 h, and day 3 of the experiment (P < 0.05). Friedman's test of multiple comparisons revealed significant differences in the PP among various time intervals for laser (chi-square = 173.407, P = 0.000) and placebo (chi-square = 184.712, P = 0.000) groups. In both groups, pain was highest at 6 and 30 h after placing elastomeric separators. No gender differences were observed in both groups. More pain was recorded in the mandible (P < 0.05) at 24 (laser group) and 30 h (both groups) after starting the experiment. The PP was significantly higher (P < 0.05) for the group aged 18 years or more, only at days 3 [both groups] and 4 [laser group only] of the experiment. The 810-nm continuous wave LLLT significantly reduced the PP in the first 3 days after orthodontic separation. However, the mean postseparation PP in both groups was low and wide ranges of PP scores were observed. © 2013 Springer-Verlag.


Uckun F.M.,Childrens Hospital Los Angeles CHLA | Uckun F.M.,University of Southern California | Myers D.E.,Childrens Hospital Los Angeles CHLA | Cheng J.,University of Illinois at Urbana - Champaign | And 2 more authors.
EBioMedicine | Year: 2015

This study was designed to improve the efficacy of radiation therapy against radiation-resistant leukemia. We report that the potency of low dose radiation therapy against B-precursor acute lymphoblastic leukemia (BPL) can be markedly enhanced by combining radiation with a liposomal nanoparticle (LNP) formulation of the SYK-P-site inhibitor C61 ("C61-LNP"). C61-LNP plus low dose total body irradiation (TBI) was substantially more effective than TBI alone or C61-LNP alone in improving the event-free survival outcome NOD/SCID mice challenged with an otherwise invariably fatal dose of human ALL xenograft cells derived from relapsed BPL patients. C61-LNP plus low dose TBI also yielded progression-free survival, tumor-free survival and overall survival outcomes in CD22δE12. ×. BCR-ABL double transgenic mice with advanced stage, radiation-resistant BPL with lymphomatous features that were significantly superior to those of mice treated with TBI alone or C61-LNP alone. © 2015.


Uckun F.M.,Childrens Hospital Los Angeles CHLA | Uckun F.M.,University of Southern California | Ma H.,Childrens Hospital Los Angeles CHLA | Cheng J.,University of Illinois at Urbana - Champaign | And 3 more authors.
British Journal of Haematology | Year: 2015

B-precursor acute lymphoblastic leukaemia (BPL) is the most common form of cancer in children and adolescents. Our recent studies have demonstrated that CD22ΔE12 is a characteristic genetic defect of therapy-refractory clones in paediatric BPL and implicated the CD22ΔE12 genetic defect in the aggressive biology of relapsed or therapy-refractory paediatric BPL. The purpose of the present study is to evaluate the biological significance of the CD22ΔE12 molecular lesion in BPL and determine if it could serve as a molecular target for RNA interference (RNAi) therapy. Here we report a previously unrecognized causal link between CD22ΔE12 and aggressive biology of human BPL cells by demonstrating that siRNA-mediated knockdown of CD22ΔE12 in primary leukaemic B-cell precursors is associated with a marked inhibition of their clonogenicity. Additionally, we report a nanoscale liposomal formulation of CD22ΔE12-specific siRNA with potent in vitro and in vivo anti-leukaemic activity against primary human BPL cells as a first-in-class RNAi therapeutic candidate targeting CD22ΔE12. © 2015 John Wiley & Sons Ltd.


Uckun F.M.,Childrens Hospital Los Angeles CHLA | Uckun F.M.,University of Southern California | Qazi S.,Childrens Hospital Los Angeles CHLA | Qazi S.,Gustavus Adolphus College | And 3 more authors.
EBioMedicine | Year: 2014

The purposes of the present study were to further evaluate the biologic significance of the CD22δE12 molecular lesion and determine if it could serve as a molecular target for RNA interference (RNAi) therapy. We show that both pediatric and adult B-lineage lymphoid malignancies are characterized by a very high incidence of the CD22δE12 genetic defect. We provide unprecedented experimental evidence for a previously unrecognized causal link between CD22δE12 and aggressive biology of BPL cells by demonstrating that siRNA-mediated knockdown of CD22δE12 in primary BPL cells is associatedwith amarked inhibition of their clonogenicity. These findings provide the preclinical proof-of-concept that siRNA-mediated depletion of CD22δE12 may help develop effective treatments for high-risk and relapsed BPL patients who are in urgent need for therapeutic innovations. We also describe a unique polypeptide-based nanoparticle formulation of CD22δE12-siRNA as an RNAi therapeutic candidate targeting CD22δE12 that is capable of delivering its siRNA cargo into the cytoplasmof leukemia cells causing effective CD22δE12 depletion andmarked inhibition of leukemic cell growth. Further development and optimization of this nanoparticle or other nanoformulation platforms for CD22δE12-siRNAmay facilitate the development of an effective therapeutic RNAi strategy against a paradigm shift in therapy of aggressive or chemotherapy-resistant B-lineage lymphoid malignancies. © 2014 The Authors.


PubMed | Gustavus Adolphus College, Childrens Hospital Los Angeles CHLA, University of Illinois at Urbana - Champaign, University of Southern California and Retrotherapy, Llc
Type: Journal Article | Journal: EBioMedicine | Year: 2015

CD22E12 has emerged as a driver lesion in the pathogenesis of pediatric B-lineage acute lymphoblastic leukemia (ALL) and a new molecular target for RNA therapeutics. Here we report a 43-gene CD22E12 signature transcriptome that shows a striking representation in primary human leukemia cells from patients with relapsed BPL. Our data uniquely indicate that CD22E12 is a candidate driver lesion responsible for the activation of MAPK and PI3-K pathways in aggressive forms of B-lineage ALL. We also show that the forced expression of a CD22 RNA trans-splicing molecule (RTM) markedly reduces the capacity of the leukemic stem cell fraction of CD22E12(+) B-lineage ALL cells to engraft and cause overt leukemia in NOD/SCID mice. We have successfully complexed our rationally designed lead CD22-RTM with PVBLG-8 to prepare a non-viral nanoscale formulation of CD22E12-RTM with potent anti-cancer activity against CD22E12(+) B-lineage leukemia and lymphoma cells. CD22-RTM nanoparticles effectively delivered the CD22-RTM cargo into B-lineage ALL cells and exhibited significant anti-leukemic activity in vitro.


PubMed | Gustavus Adolphus College, Childrens Hospital Los Angeles CHLA, University of Southern California and University of Illinois at Urbana - Champaign
Type: Journal Article | Journal: EBioMedicine | Year: 2015

This study was designed to improve the efficacy of radiation therapy against radiation-resistant leukemia. We report that the potency of low dose radiation therapy against B-precursor acute lymphoblastic leukemia (BPL) can be markedly enhanced by combining radiation with a liposomal nanoparticle (LNP) formulation of the SYK-P-site inhibitor C61 (C61-LNP). C61-LNP plus low dose total body irradiation (TBI) was substantially more effective than TBI alone or C61-LNP alone in improving the event-free survival outcome NOD/SCID mice challenged with an otherwise invariably fatal dose of human ALL xenograft cells derived from relapsed BPL patients. C61-LNP plus low dose TBI also yielded progression-free survival, tumor-free survival and overall survival outcomes in CD22E12BCR-ABL double transgenic mice with advanced stage, radiation-resistant BPL with lymphomatous features that were significantly superior to those of mice treated with TBI alone or C61-LNP alone.


Uckun F.M.,Childrens Hospital Los Angeles CHLA | Uckun F.M.,University of Southern California | Qazi S.,Childrens Hospital Los Angeles CHLA | Qazi S.,Gustavus Adolphus College | And 3 more authors.
Integrative Biology (United Kingdom) | Year: 2015

Our recent studies have demonstrated that the CD22 exon 12 deletion (CD22ΔE12) is a characteristic genetic defect of therapy-refractory clones in pediatric B-precursor acute lymphoblastic leukemia (BPL) and implicated the CD22ΔE12 genetic defect in the aggressive biology of relapsed or therapy-refractory pediatric BPL. The purpose of the present study was to further evaluate the biologic significance of the CD22ΔE12 molecular lesion and determine if it could serve as a molecular target for corrective repair using RNA trans-splicing therapy. We show that both pediatric and adult B-lineage lymphoid malignancies are characterized by a very high incidence of the CD22ΔE12 genetic defect. We provide experimental evidence that the correction of the CD22ΔE12 genetic defect in human CD22ΔE12+ BPL cells using a rationally designed CD22 RNA trans-splicing molecule (RTM) caused a pronounced reduction of their clonogenicity. The RTM-mediated correction replaced the downstream mutation-rich segment of Intron 12 and remaining segments of the mutant CD22 pre-mRNA with wildtype CD22 exons 10-14, thereby preventing the generation of the cis-spliced aberrant CD22ΔE12 product. The anti-leukemic activity of this RTM against BPL xenograft clones derived from CD22ΔE12+ leukemia patients provides the preclinical proof-of-concept that correcting the CD22ΔE12 defect with rationally designed CD22 RTMs may provide the foundation for therapeutic innovations that are needed for successful treatment of high-risk and relapsed BPL patients. This journal is © The Royal Society of Chemistry 2015.


Sheard M.A.,Childrens Hospital Los Angeles CHLA | Asgharzadeh S.,Childrens Hospital Los Angeles CHLA | Asgharzadeh S.,University of Southern California | Asgharzadeh S.,Childrens Oncology Group | And 9 more authors.
Journal of Immunotherapy | Year: 2013

Neuroblastoma cells have been reported to be resistant to death induced by soluble, recombinant forms of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (CD253/TNFSF10) because of low or absent expression of caspase-8 and/or TRAIL-receptor 2 (TRAIL-R2/DR5/CD262/TNFRSF10b). However, their sensitivity to membrane-bound TRAIL on natural killer (NK) cells is not known. Comparing microarray gene expression and response to NK cell-mediated cytotoxicity, we observed a correlation between TRAIL-R2 expression and the sensitivity of 14 neuroblastoma cell lines to the cytotoxicity of NK cells activated with interleukin (IL)-2 plus IL-15. Even though most NK cytotoxicity was dependent upon perforin, the cytotoxicity was supplemented by TRAIL in 14 of 17 (82%) neuroblastoma cell lines as demonstrated using an anti-TRAIL neutralizing antibody. Similarly, a recently developed NK cell expansion system employing IL-2 plus lethally irradiated K562 feeder cells constitutively expressing membrane-bound IL-21 (K562 clone 9.mbIL21) resulted in activated NK cells derived from normal healthy donors and neuroblastoma patients that also utilized TRAIL to supplement cytotoxicity. Exogenous interferon-γ upregulated expression of caspase-8 in 3 of 4 neuroblastoma cell lines and increased the contribution of TRAIL to NK cytotoxicity against 2 of the 3 lines; however, relatively little inhibition of cytotoxicity was observed when activated NK cells were treated with an anti-interferon-γ neutralizing antibody. Constraining the binding of anti-TRAIL neutralizing antibody to membrane-bound TRAIL but not soluble TRAIL indicated that membrane-bound TRAIL alone was responsible for essentially all of the supplemental cytotoxicity. Together, these findings support a role for membrane-bound TRAIL in the cytotoxicity of NK cells against neuroblastoma cells. © 2013 by Lippincott Williams & Wilkins.


Uckun F.M.,Childrens Hospital Los Angeles CHLA | Uckun F.M.,University of Southern California | Myers D.E.,Childrens Hospital Los Angeles CHLA | Ma H.,Childrens Hospital Los Angeles CHLA | And 3 more authors.
EBioMedicine | Year: 2015

In high-risk remission B-precursor acute lymphoblastic leukemia (BPL) patients, relapse rates have remained high post-hematopoietic stem cell transplantation (HSCT) even after the use of very intensive total body irradiation (TBI)-based conditioning regimens, especially in patients with a high "minimal residual disease" (MRD) burden. New agents capable of killing radiation-resistant BPL cells and selectively augmenting their radiation sensitivity are therefore urgently needed. We report preclinical proof-of-principle that the potency of radiation therapy against BPL can be augmented by combining radiation with recombinant human CD19-Ligand×soluble TRAIL ("CD19L-sTRAIL") fusion protein. CD19L-sTRAIL consistently killed radiation-resistant primary leukemia cells from BPL patients as well as BPL xenograft cells and their leukemia-initiating in vivo clonogenic fraction. Low dose total body irradiation (TBI) combined with CD19L-sTRAIL was highly effective against (1) xenografted CD19+ radiochemotherapy-resistant human BPL in NOD/SCID (NS) mice challenged with an otherwise invariably fatal dose of xenograft cells derived from relapsed BPL patients as well as (2) radiation-resistant advanced stage CD19+ murine BPL with lymphomatous features in CD22δE12xBCR-ABL double transgenic mice. We hypothesize that the incorporation of CD19L-sTRAIL into the pre-transplant TBI regimens of patients with very high-risk BPL will improve their survival outcome after HSCT. © 2015.


PubMed | Gustavus Adolphus College, Childrens Hospital Los Angeles CHLA, University of Southern California and Rose Pathology Services LLC
Type: Journal Article | Journal: EBioMedicine | Year: 2015

In high-risk remission B-precursor acute lymphoblastic leukemia (BPL) patients, relapse rates have remained high post-hematopoietic stem cell transplantation (HSCT) even after use of very intensive total body irradiation (TBI)-based conditioning regimens, especially in patients with a high minimal residual disease (MRD) burden. New agents capable of killing radiation-resistant BPL cells and selectively augmenting their radiation sensitivity are therefore urgently needed. We report preclinical proof-of-principle that the potency of radiation therapy against BPL can be augmented by combining radiation with recombinant human CD19-Ligand soluble TRAIL (CD19L-sTRAIL) fusion protein. CD19L-sTRAIL consistently killed radiation-resistant primary leukemia cells from BPL patients as well as BPL xenograft cells and their leukemia-initiating

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