Histone deacetylase inhibitor pracinostat suppresses colorectal cancer by inducing CDK5-Drp1 signaling-mediated peripheral mitofission / 药物分析学报

Divisions at the periphery and midzone of mitochondria are two fission signatures that determine the fate of mitochondria and cells.Pharmacological induction of excessively asymmetric mitofission-associated cell death(MFAD)by switching the scission position from the mitochondrial midzone to the periphery represents a promising strategy for anticancer therapy.By screening a series of pan-inhibitors,we identified pracinostat,a pan-histone deacetylase(HDAC)inhibitor,as a novel MFAD inducer,that exhibited a significant anticancer effect on colorectal cancer(CRC)in vivo and in vitro.Pracinostat increased the expression of cyclin-dependent kinase 5(CDK5)and induced its acetylation at residue lysine 33,accelerating the formation of complex CDK5/CDK5 regulatory subunit 1 and dynamin-related protein 1(Drp1)-mediated mitochondrial peripheral fission.CRC cells with high level of CDK5(CDK5-high)displayed midzone mitochondrial division that was associated with oncogenic phenotype,but treatment with pracinostat led to a lethal increase in the already-elevated level of CDK5 in the CRC cells.Mechanistically,pracinostat switched the scission position from the mitochondrial midzone to the periphery by improving the binding of Drp1 from mitochondrial fission factor(MFF)to mitochondrial fission 1 protein(FIS1).Thus,our results revealed the anticancer mechanism of HDACi pracinostat in CRC via activating CDK5-Drp1 signaling to cause selective MFAD of those CDK5-high tumor cells,which implicates a new paradigm to develop potential therapeutic strategies for CRC treatment.

Clinical study on childhood acute lymphoblastic leukemia diagnosed and treated with 04 Protocol in Chongqing, China / 中华儿科杂志

<p><b>OBJECTIVE</b>To analyze the clinical and laboratory data from acute lymphoblastic leukemia (ALL) patients and the results of treatment using 04 Protocol (suggested by the Pediatric Hematology Group of Chinese Medical Association in 2004).</p><p><b>METHODS</b>This study included 88 children with ALL below the age of 18 years during the period from October 1, 2004 to June 30, 2007. Minimal inhibitory concentration (MIC) and clinical risk classification were done and the new chemotherapy regimen was used according to the protocol. Patients were stratified into low-risk (LR), medium-risk (MR), and high-risk (HR) groups. Life table method was used to estimate survival rate and statistical analysis was done by using software SPSS for Windows.</p><p><b>RESULTS</b>From October 2004 to June 2007, 88 childhood ALL patients were treated with the 04 Protocol. Sixty-three (91.30%) patients attained complete remission (CR) and 17 patients lost to follow up. The overall 4-year-event-free survival (EFS) rate (+/- SE) was (59.73 +/- 7.22)%. EFS was (75.60 +/- 9.71)% in the LR (n = 30), (65.50 +/- 11.69)% in the MR (n = 20) and (44.03 +/- 12.36)% in the HR. Relapse occurred in 18.18% of patients. Seven (7.95%) of 88 patients with ALL died during he induction therapy. Infection was the most common cause of death.</p><p><b>CONCLUSION</b>The outcome of patients treated with the 04 Protocol was favorable. Clinical risk classification and the leukemia cells of D19 are independent predictors of prognosis of ALL. High dose methotrexate played an important role in prevention and treatment of central nervous system leukemia. The mortality rate of this chemotherapeutic protocol during induction therapy was high.</p>

Pars plana vitrectomy and internal limiting membrane peeling for macular oedema secondary to retinal vein occlusion: a pilot study

<p><b>INTRODUCTION</b>Macular oedema is the main cause of visual impairment following retinal vein occlusion. The purpose of this study was to evaluate the anatomical and functional outcome of pars plana vitrectomy and internal limited membrane (ILM) peeling for macular oedema secondary to retinal vein occlusion.</p><p><b>CLINICAL PICTURE</b>This pilot study is a prospective nonrandomised series of 11 eyes of 11 patients with macular oedema secondary to retinal vein occlusion. The best-corrected visual acuity (BCVA), foveal thickness on optical coherence tomography, fundus fluorescein angiography (FFA) and multifocal electroretinography were evaluated.</p><p><b>TREATMENT AND OUTCOME</b>All 11 patients underwent pars plana vitrectomy with ILM peeling. The mean postoperative follow-up was 13.5 months (range, 1.5 to 24). The mean thickness at the foveal centre decreased from 794 +/- 276 microm preoperatively to 373 +/- 150 microm, 302 +/- 119 microm, 249 +/- 203 microm and 185 +/- 66 microm at 1 week, 1 month, 3 months and the final visit postoperatively, respectively (all P <0.001, paired t- test, compared to preoperative thickness). Postoperative FFA demonstrated markedly reduced leakage in the macular region. At the final visit, BCVA improved 2 lines or more in 72.7% (8/11) of patients and was unchanged in 27.3% (3/11) patients. Complications included cataract in 7 patients and vitreous haemorrhage, recurrence of macular oedema and visual field defect in 1 case each.</p><p><b>CONCLUSION</b>Pars plana vitrectomy and ILM peeling rapidly reduced the macular oedema caused by retinal vein occlusion, with improvement in BCVA.</p>