Effect of Photobiomodulation on Vinblastine-Poisoned Murine HERS Cells

Objective: The aim of this study was to investigate the effect of near-infrared (NIR) photobiomodulation on the proliferation and glutathione levels in murine Hertwig\u27s epithelial root sheath (HERS) cells after poisoning with vinblastine. Background: Photobiomodulation has been shown to improve wound healing in a number of animal models. There have been no studies on the effect of photobiomodulation on cancer-related chemotherapy injury to the cells that initiate tooth root growth. Materials and Methods: Control groups consisted of murine HERS cells without vinblastine (VB−) and cells with vinblastine at 10, 20, and 30 ng/mL (VB10, VB20, and VB30). Experimental groups consisted of these same groups with light therapy (VB-L, VB10L, VB20L, and VB30L). The cells were exposed to vinblastine for 1 h. Photobiomodulation consisted of a 75-cm2 gallium-aluminum-arsenide light-emitting diode (LED) array at an energy density of 12.8 J/cm2, delivered with 50 mW/cm2 power over 256 s. Results: Vinblastine alone significantly decreased HERS cell proliferation and glutathione levels at all concentrations (VB10 [−55%, p \u3c 1.0 × 10−8]; VB20 [−72%, p \u3c 1.0 × 10−9]; VB30 [−80%, p \u3c 1.0 × 10−10]; and VB10 [−36%, p \u3c 0.0001]; VB20 [−49%, p \u3c 1.0 × 10−6]; VB30 [−53%, p \u3c 1.0 × 10−7] respectively). Photobiomodulation significantly increased cell proliferation at all levels of vinblastine exposure (VB10L [+50%, p \u3c 0.0001]; VB20L [+45%, p \u3c 0.05]; VB30 [+39%, p \u3c 0.05]) but not of the control (+22%, p  = 0.063). The photobiomodulation significantly increased glutathione production in all concentrations of vinblastine except 20 ng/mL (VB10L [+39%, p = 0.007]; VB20L [+19%, p = 0.087]; VB30 [+14%, p = 0.025]) and the control (+12%, p = 0.13). Conclusions: Photobiomodulation demonstrated an improvement in proliferation and glutathione levels in vinblastine-poisoned murine HERS cells

Clay-kickers of Flanders Fields: Canadian Tunnellers at Messines Ridge 1916-1917

This article explores the Canadian tunnelling companies’ military mining organisation and accomplishments in underground galleries during the Great War. This comprehensive study explains the crucial role played by the Canadian engineers, in conjunction with British and Australian engineers, in the successful detonation of nineteen deep mines at Messines Ridge, Belgium on 7 June 1917. The tunnellers’ perseverance and skill were evident that morning when they slammed home plungers and threw switches igniting the largest planned explosion up to that time. However, daily hardships and dangers of underground warfare from the claustrophobic environment to the stress from the eavesdropping enemy led to disciplinary action including Field Punishment No. 1

Pulse-Administered Toceranib Phosphate Plus Lomustine for Treatment of Unresectable Mast Cell Tumors in Dogs.

BackgroundNonresectable mast cell tumors (MCT) in dogs remain a therapeutic challenge, and investigation of novel combination therapies is warranted. Intermittent administration of tyrosine kinase inhibitors (TKI) combined with cytotoxic chemotherapy may effectively chemosensitize canine MCT while decreasing cost and adverse effects associated with either agent administered as monotherapy.Hypothesis/objectivesThe primary study objectives were to (1) identify the maximally tolerated dose (MTD), (2) determine the objective response rate (ORR) and (3) describe the adverse event profile of pulse-administered toceranib phosphate (TOC) combined with lomustine.AnimalsForty-seven client-owned dogs with measurable MCT.MethodsToceranib phosphate was given PO on days 1, 3 and 5 of a 21-day cycle at a target dosage of 2.75 mg/kg. Lomustine was given PO on day 3 of each cycle at a starting dosage of 50 mg/m(2) . All dogs were concurrently treated with diphenhydramine, omeprazole, and prednisone.ResultsThe MTD of lomustine was established at 50 mg/m(2) when combined with pulse-administered TOC; the dose-limiting toxicity was neutropenia. Forty-one dogs treated at the MTD were evaluable for outcome assessment. The ORR was 46% (4 complete response, 15 partial response) and the overall median progression-free survival (PFS) was 53 days (1 to >752 days). On multivariate analysis, variables significantly associated with improved PFS included response to treatment, absence of metastasis, and no previous chemotherapy.Conclusions and clinical importanceCombined treatment with pulse-administered TOC and lomustine generally is well tolerated and may be a reasonable treatment option for dogs with unresectable or metastatic MCT

Predictive value of hematological and phenotypical parameters on postchemotherapy leukocyte recovery

Background: Grade IV chemotherapy toxicity is defined as absolute neutrophil count <500/μL. The nadir is considered as the lowest neutrophil number following chemotherapy, and generally is not expected before the 7th day from the start of chemotherapy. The usual prophylactic dose of rHu-G-CSF (Filgrastim) is 300 μg/day, starting 24-48 h after chemotherapy until hematological recovery. However, individual patient response is largely variable, so that rHu-G-CSF doses can be different. The aim of this study was to verify if peripheral blood automated flow cytochemistry and flow cytometry analysis may be helpful in predicting the individual response and saving rHu-G-CSF. Methods: During Grade IV neutropenia, blood counts from 30 cancer patients were analyzed daily by ADVIA 120 automated flow cytochemistry analyzer and by Facscalibur flow cytometer till the nadir. "Large unstained cells" (LUCs), myeloperoxidase index (MPXI), blasts, and various cell subpopulations in the peripheral blood were studied. At nadir rHu-G-CSF was started and 81 chemotherapy cycles were analyzed. Cycles were stratified according to their number and to two dose-levels of rHuG-CSF needed to recovery (300-600 vs. 900-1200 μg) and analyzed in relation to mean values of MPXI and mean absolute number of LUCs in the nadir phase. The linear regressions of LUCs % over time in relation to two dose-levels of rHu-G-CSF and uni-multivariate analysis of lymphocyte subpopulations, CD34+ cells, MPXI, and blasts were also performed. Results: In the nadir phase, the increase of MPXI above the upper limit of normality (>10; median 27.7), characterized a slow hematological recovery. MPXI levels were directly related to the cycle number and inversely related to the absolute number of LUCs and CD34 +/CD45+ cells. A faster hematological recovery was associated with a higher LUC increase per day (0.56% vs. 0.25%), higher blast (median 36.7/μL vs. 19.5/μL) and CD34+/CD45+ cell (median 2.2/μL vs. 0.82/μL) counts. Conclusions: Our study showed that some biological indicators such as MPXI, LUCs, blasts, and CD34 +/CD45+ cells may be of clinical relevance in predicting individual hematological response to rHu-G-CSF. Special attention should be paid when nadir MPXI exceeds the upper limit of normality because the hematological recovery may be delayed. © 2009 Clinical Cytometry Society

Cisplatin-based chemotherapy of testicular cancer - Two decades after a major breakthrough

Two decades ago the introduction of cisplatin-based combination chemotherapy has dramatically improved the prognosis of patients with metastatic testicular cancer, At present 3 cycles of cisplatin, etoposide and bleomycin are considered as standard treatment for good-risk metastatic disease. Outside of clinical trials patients in the intermediate and poor prognosis categories should receive 4 cycles of this standard regimen, Clinical trials currently evaluate the role of high-dose chemotherapy in first-line treatment of high-risk patients and in the salvage setting, Post-chemotherapy resection of tumor residuals remains an important part of therapy. Attention should be focused on long-term toxicity of therapy and the occurrence of late relapse

Clay-kickers of Flanders Fields: Canadian Tunnellers at Messines Ridge 1916-1917

This article explores the Canadian tunnelling companies’ military mining organisation and accomplishments in underground galleries during the Great War. This comprehensive study explains the crucial role played by the Canadian engineers, in conjunction with British and Australian engineers, in the successful detonation of nineteen deep mines at Messines Ridge, Belgium on 7 June 1917. The tunnellers’ perseverance and skill were evident that morning when they slammed home plungers and threw switches igniting the largest planned explosion up to that time. However, daily hardships and dangers of underground warfare from the claustrophobic environment to the stress from the eavesdropping enemy led to disciplinary action including Field Punishment No. 1

Paclitaxel resistance by random mutagenesis of α‐tubulin

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102075/1/cm21154-sup-0001-suppfig1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/102075/2/cm21154-sup-0002-suppfig2.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/102075/3/cm21154.pd

Investigation of the marine compound spongistatin 1 links the inhibition of PKCα translocation to nonmitotic effects of tubulin antagonism in angiogenesis

The aims of the study were to meet the demand of new tubulin antagonists with fewer side effects by characterizing the antiangiogenic properties of the experimental compound spongistatin 1, and to elucidate nonmitotic mechanisms by which tubulin antagonists inhibit angiogenesis. Although tubulin-inhibiting drugs and their antiangiogenic properties have been investigated for a long time, surprisingly little is known about their underlying mechanisms of action. Antiangiogenic effects of spongistatin 1 were investigated in endothelial cells in vitro, including functional cell-based assays, live-cell imaging, and a kinome array, and in the mouse cornea pocket assay in vivo. Spongistatin 1 inhibited angiogenesis at nanomolar concentrations (IC50: cytotoxicity>50 nM, proliferation 100 pM, migration 1.0 nM, tube formation 1.0 nM, chemotaxis 1.0 nM, aortic ring sprouting 500 pM, neovascularization in vivo 10 μg/kg). Further, a kinome array and validating data showed that spongistatin 1 inhibits the phosphorylation activity of protein kinase Cα (PKCα), an essential kinase in angiogenesis, and its translocation to the membrane. Thus, we conclude that PKCα might be an important target for the antiangiogenic effects of tubulin antagonism. In addition, the data from the kinase array suggest that different tubulin antagonists might have individual intracellular actions.—Rothmeier, A. S., Ischenko, I., Joore, J., Garczarczyk, D., Fu¨rst, R., Bruns, C. J., Vollmar, A. M., Zahler, S. Investigation of the marine compound spongistatin 1 links the inhibition of PKCα translocation to nonmitotic effects of tubulin antagonism in angiogenesis