Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG

Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. CBL0137 is an anti-cancer compound developed from quinacrine that targets facilitates chromatin transcription (FACT), a chromatin remodeling complex involved in transcription, replication, and DNA repair. We show that CBL0137 displays profound cytotoxic activity against a panel of patient-derived DIPG cultures by restoring tumor suppressor TP53 and Rb activity. Moreover, in an orthotopic model of DIPG, treatment with CBL0137 significantly extends animal survival. The FACT subunit SPT16 is found to directly interact with H3.3K27M, and treatment with CBL0137 restores both histone H3 acetylation and trimethylation. Combined treatment of CBL0137 with the histone deacetylase inhibitor panobinostat leads to inhibition of the Rb/E2F1 pathway and induction of apoptosis. The combination of CBL0137 and panobinostat significantly prolongs the survival of mice bearing DIPG orthografts, suggesting a potential treatment strategy for DIPG

An NF-κB and Slug Regulatory Loop Active in Early Vertebrate Mesoderm

BACKGROUND: In both Drosophila and the mouse, the zinc finger transcription factor Snail is required for mesoderm formation; its vertebrate paralog Slug (Snai2) appears to be required for neural crest formation in the chick and the clawed frog Xenopus laevis. Both Slug and Snail act to induce epithelial to mesenchymal transition (EMT) and to suppress apoptosis. METHODOLOGY & PRINCIPLE FINDINGS: Morpholino-based loss of function studies indicate that Slug is required for the normal expression of both mesodermal and neural crest markers in X. laevis. Both phenotypes are rescued by injection of RNA encoding the anti-apoptotic protein Bcl-xL; Bcl-xL's effects are dependent upon IκB kinase-mediated activation of the bipartite transcription factor NF-κB. NF-κB, in turn, directly up-regulates levels of Slug and Snail RNAs. Slug indirectly up-regulates levels of RNAs encoding the NF-κB subunit proteins RelA, Rel2, and Rel3, and directly down-regulates levels of the pro-apopotic Caspase-9 RNA. CONCLUSIONS/SIGNIFICANCE: These studies reveal a Slug/Snail–NF-κB regulatory circuit, analogous to that present in the early Drosophila embryo, active during mesodermal formation in Xenopus. This is a regulatory interaction of significance both in development and in the course of inflammatory and metastatic disease

Place of insulin therapy in current approaches to the treatment of type 2 diabetes

Type 2 diabetes mellitus (T2DM) is a high risk factor for the development of macrovascular complications. Several large studies have demonstrated the fundamental role of early extensive blood glucose control in the prevention of these complications. An aggressive approach in achieving normoglycemia in patients with T2DM and existing macrovascular complications could lead to an increase in cardiovascular outcomes, which has a clear association with hypoglycemic conditions. Insulin therapy (IT) remains one of the most effective pharmacological treatments for diabetes provided adequate and timely prescription. The advent of long-acting insulin analogues helped not only to reduce the incidence of hypoglycemia as one of the most clinically relevant adverse events of IT, but also marked certain prospects in the prevention of type 2 diabetes in people with prediabetes

BLOOD AND LYMPH CIRCULATION UNDER NORMAL CONDITIONS AND IN CIRCULATORY HYPOXIA

The aim of the study was to assess the indices of blood and lymph microcirculation in the skin in healthy men under normal condition and in circulatory hypoxia. Thirty healthy men, aged 19 to 27, were examined. Evaluation of blood and lymph circulation was carried out by laser Doppler flowmetry (LDF) of the skin - the palmar surface of the base of thumb. The results showed that in occlusal period an increase in the lymph flow and decrease in blood flow were revealed, compared to normal conditions. In post-occlusal period a rapid recovery of blood circulation and slight decrease in lymph circulation were observed. Conclusion. Indices of blood and lymph circulation differ in normal conditions, in occlusal test and in post-occlusal period. Different reactivity of blood and lymph microvessels is observed in circulation recovery. The data obtained can be used for the diagnosis of blood and lymph flow disorders and assessment of local toxicosis severity under various pathological conditions

RF patients after resection of the gall bladder – is it always postcholecystectomy syndrome?

The article analyzes the causes of recurrent abdominal pain and dyspeptic phenomena in 657 patients after cholecystectomy. The authors found out that after gall bladder resection 48% of patients complain of pain and dyspepsia. Postcholecystectomy syndrome (dysfunction of Oddi’s sphincter) is diagnosed in 15.2% of the patients. The proportion of diseases of the esophagus and organs of the gastroduodenal zone is 36.4%, of the hepato-pancreato-biliary one is 38.3 per cent. Diagnostic errors at the preoperative stage and/or tactical ones during cholecystectomy amounted to 7.8%

CENTRAL PONTINE MYELINOLYSIS AFTER ORTHOTOPIC LIVER TRANSPLANTATION (TWO CASE REPORTS)

Central pontine myelinolysis (CPM) is the rare, but extremely severe complication after orthotopic liver trans- plantation. The reason for CPM is currently not precisely defined. However, the rapid correction of hyponatremia is considered as the main etiological factor. In this paper we present two clinical cases of CPM in patients under- went orthotopic liver transplantation. We also discuss the pathophysiology, epidemiology, clinical presentation, treatment options and preventive measures of CPM