Progressive cavitating leukoencephalopathy: Case report of a rare childhood onset neurodegenerative disease

The leukoencephalopathies with cystic changes form a distinct subtype of childhood onset neurodegenerativedisorders. This group has heterogeneous etiological differentials that primarily include mitochondrial disorders, someleukodystrophies and central nervous system infections. We report this case of a 17-month old girl who presented withseizures, episodic encephalopathy, elevated blood lactate level and lactate peak on magnetic resonance spectroscopy,a typical imaging picture noted on cranial magnetic resonance imaging and absence of deletions or duplications ofmitochondrial deoxyribonucleic acid. Progressive cavitating leukoencephalopathy (PCL) is a recently described entitywith only a few cases reported so far. We report the first case of PCL from India. Accurate diagnosis can be made, notonly, by the presence of typical clinicoradiological findings of PCL, but also by the awareness of, and, ruling out of,the various other differential diagnoses that are discussed in detail below

Synergistic Antitumor Effects of Novel HDAC Inhibitors and Paclitaxel In Vitro and In Vivo

Preclinical studies support the therapeutic potential of histone deacetylases inhibitors (HDACi) in combination with taxanes. The efficacy of combination has been mainly ascribed to a cooperative effect on microtubule stabilization following tubulin acetylation. In the present study we investigated the effect of paclitaxel in combination with two novel HDACi, ST2782 or ST3595, able to induce p53 and tubulin hyperacetylation. A synergistic effect of the paclitaxel/ST2782 (or ST3595) combination was found in wild-type p53 ovarian carcinoma cells, but not in a p53 mutant subline, in spite of a marked tubulin acetylation. Such a synergistic interaction was confirmed in additional human solid tumor cell lines harboring wild-type p53 but not in those expressing mutant or null p53. In addition, a synergistic cytotoxic effect was found when ST2782 was combined with the depolymerising agent vinorelbine. In contrast to SAHA, which was substantially less effective in sensitizing cells to paclitaxel-induced apoptosis, ST2782 prevented up-regulation of p21WAF1/Cip1 by paclitaxel, which has a protective role in response to taxanes, and caused p53 down-regulation, acetylation and mitochondrial localization of acetylated p53. The synergistic antitumor effects of the paclitaxel/ST3595 combination were confirmed in two tumor xenograft models. Our results support the relevance of p53 modulation as a major determinant of the synergistic interaction observed between paclitaxel and novel HDACi and emphasize the therapeutic interest of this combination

Excessive HDAC activation is critical for neurodegeneration in the rd1 mouse

Inherited retinal degenerations, collectively termed retinitis pigmentosa (RP), constitute one of the leading causes of blindness in the developed world. RP is at present untreatable and the underlying neurodegenerative mechanisms are unknown, even though the genetic causes are often established. Acetylation and deacetylation of histones, carried out by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively, affects cellular division, differentiation, death and survival. We found acetylation of histones and probably other proteins to be dramatically reduced in degenerating photoreceptors in the rd1 human homologous mouse model for RP. Using a custom developed in situ HDAC activity assay, we show that overactivation of HDAC classes I/II temporally precedes photoreceptor degeneration. Moreover, pharmacological inhibition of HDACs I/II activity in rd1 organotypic retinal explants decreased activity of poly-ADP-ribose-polymerase and strongly reduced photoreceptor cell death. These findings highlight the importance of protein acetylation for photoreceptor cell death and survival and propose certain HDAC classes as novel targets for the pharmacological intervention in RP

Comparative analysis of novel and conventional Hsp90 inhibitors on HIF activity and angiogenic potential in clear cell renal cell carcinoma: implications for clinical evaluation

<p>Abstract</p> <p>Background</p> <p>Perturbing Hsp90 chaperone function targets hypoxia inducible factor (HIF) function in a von Hippel-Lindau (VHL) independent manner, and represents an approach to combat the contribution of HIF to cell renal carcinoma (CCRCC) progression. However, clinical trials with the prototypic Hsp90 inhibitor 17-AAG have been unsuccessful in halting the progression of advanced CCRCC.</p> <p>Methods</p> <p>Here we evaluated a novel next generation small molecule Hsp90 inhibitor, EC154, against HIF isoforms and HIF-driven molecular and functional endpoints. The effects of EC154 were compared to those of the prototypic Hsp90 inhibitor 17-AAG and the histone deacetylase (HDAC) inhibitor LBH589.</p> <p>Results</p> <p>The findings indicate that EC154 is a potent inhibitor of HIF, effective at doses 10-fold lower than 17-AAG. While EC154, 17-AAG and the histone deacetylase (HDAC) inhibitor LBH589 impaired HIF transcriptional activity, CCRCC cell motility, and angiogenesis; these effects did not correlate with their ability to diminish HIF protein expression. Further, our results illustrate the complexity of HIF targeting, in that although these agents suppressed HIF transcripts with differential dynamics, these effects were not predictive of drug efficacy in other relevant assays.</p> <p>Conclusions</p> <p>We provide evidence for EC154 targeting of HIF in CCRCC and for LBH589 acting as a suppressor of both HIF-1 and HIF-2 activity. We also demonstrate that 17-AAG and EC154, but not LBH589, can restore endothelial barrier function, highlighting a potentially new clinical application for Hsp90 inhibitors. Finally, given the discordance between HIF activity and protein expression, we conclude that HIF expression is not a reliable surrogate for HIF activity. Taken together, our findings emphasize the need to incorporate an integrated approach in evaluating Hsp90 inhibitors within the context of HIF suppression.</p

&#x2032;Sure closure&#x2032;-skin stretching system, our clinical experience

<b>Objective:</b> In clinical practice of reconstructive surgery one of the problems one routinely comes across is skin and soft tissue defects, which require coverage. Coverage of such wounds requires primary/secondary closure, skin grafting or flaps. The objective of our clinical series was to assess the efficacy of sure closure skin stretching system for closure of defects which otherwise would have required major flap cover or skin grafting. <b> Methods:</b> Our series included five patients with different causes and types of wound defects namely: 1. Post-traumatic soft tissue defect on dorsum of hand. 2. Post fasciotomy wound on leg (anterolateral aspect). 3. Abdominal wound dehiscence following surgery for enterocutaneous fistula. 4. Leg soft tissue defect following dehiscence of fasciocutaneous flap. 5. Secondary defect following harvesting a lateral arm/forearm free flap. The device was applied to skin edges after preparing the wound under local anesthesia and the skin edges were brought together by turning the skin-stretching knob. After adequate approximation of the edges of the wound it was sutured by conventional suturing techniques. Results: All the wounds could be successfully closed using the skin stretching system in our series. The time taken for the closure ranged from 2 to 48 h. <b> Conclusions:</b> Sure closure skin stretching system is an effective device for closing some of the skin defects which otherwise would have required skin flaps or grafts. In all the patients wound closure could be achieved by this method and was carried out under local anesthesia. Use of this technique is simple and helps to reduce the morbidity and cost of treatment by allowing the reconstructive surgeon to avoid using major flaps or grafts