Metabolism of [U‐13C]glucose in human brain tumors in vivo

Glioblastomas and brain metastases demonstrate avid uptake of 2‐[¹⁸F]fluoro‐2‐deoxyglucose by positron emission tomography and display perturbations of intracellular metabolite pools by ¹H MRS. These observations suggest that metabolic reprogramming contributes to brain tumor growth in vivo. The Warburg effect, excess metabolism of glucose to lactate in the presence of oxygen, is a hallmark of cancer cells in culture. 2‐[¹⁸F]Fluoro‐2‐deoxyglucose‐positive tumors are assumed to metabolize glucose in a similar manner, with high rates of lactate formation relative to mitochondrial glucose oxidation, but few studies have specifically examined the metabolic fates of glucose in vivo. In particular, the capacity of human brain cancers to oxidize glucose in the tricarboxylic acid cycle is unknown. Here, we studied the metabolism of human brain tumors in situ. [U‐¹³ C]Glucose (uniformly labeled glucose, i.e. d ‐glucose labeled with ¹³ C in all six carbons) was infused during surgical resection, and tumor samples were subsequently subjected to ¹³C NMR spectroscopy. The analysis of tumor metabolites revealed lactate production, as expected. We also determined that pyruvate dehydrogenase, turnover of the tricarboxylic acid cycle, anaplerosis and de novo glutamine and glycine synthesis contributed significantly to the ultimate disposition of glucose carbon. Surprisingly, less than 50% of the acetyl‐coenzyme A pool was derived from blood‐borne glucose, suggesting that additional substrates contribute to tumor bioenergetics. This study illustrates a convenient approach that capitalizes on the high information content of ¹³C NMR spectroscopy and enables the analysis of intermediary metabolism in diverse cancers growing in their native microenvironment. Copyright © 2012 John Wiley & Sons, Ltd.     

Traumatic bone cyst of the mandible: a review of 26 cases

The traumatic bone cyst is characterized by the presence of an asymptomatic sinus devoid of epithelial lining, which is rarely found in the jaws.ObjectiveTo describe the clinical, surgical and radiographic findings of traumatic bone cysts.Material and MethodA retrospective study was made of patients diagnosed with traumatic bone cysts at an oral pathology department from 1992 to 2007. Data on the clinical, radiographic and surgical complications were gathered.ResultsTwenty-six cases of traumatic bone cyst were diagnosed in 15 years; 17 were male and 09 were female. Most patients were within first two decades of life and had no pain or history of trauma in the affected area. The multilocular pattern was observed in only seven cases, its radiographic appearance suggests a tumor. Air was found inside the lesion in about 70% of cases; serous fluid with blood and blood only were uncommon within the lesions.ConclusionA higher prevalence in young patients, absence of a history of trauma, and a small number of lesions containing serous fluid with blood reflects the need to discuss the true pathogenesis of traumatic bone cysts.     

Emotion complexity and emotion regulation across adulthood

This research used data from a study on daily emotional experience in adulthood to examine the associations between age, emotion complexity, and emotion regulation. Data were drawn from a study of daily stress that included 239 participants ranging in age from 18 to 89 from North Central Florida. Two indicators of emotion complexity were considered: emotion differentiation and the co-occurrence of positive and negative affect. Emotion regulation was assessed in terms of individuals’ likelihood of maintaining adaptive emotion states. There were no age differences in adults’ co-occurrence of positive and negative emotions. In contrast to theories suggesting age would be associated with greater emotion complexity, the findings revealed that older adults had lower differentiation scores than younger adults. Age was also associated with more adaptive patterns of emotion regulation. Specifically, older adults persisted in low negative states and moved out of high negative states more readily than younger adults. Finally, neuroticism, self-concept incoherence, mean daily stress, and emotion complexity were associated with emotion regulation. Notably, adults who reported a greater mix of positive and negative affect moved out of high negative affect states more rapidly than adults with lower co-occurrence scores. This finding is in keeping with a growing body of work suggesting that positive affect promotes recovery from negative affect. Overall, the findings suggest that although emotion complexity is associated with emotion regulation, it does not appear to be a key factor underlying age differences in emotion regulation.     

Activity of CD101, a long-acting echinocandin,against clinical isolates of Candida auris

CD101 is a new echinocandin with a prolonged half-life. CD101 was tested by broth microdilution against 100 isolates of the emerging yeast Candida auris. It showed activity against most isolates, including some that were resistant to other echinocandins.     

To chelate or not to chelate in MDS: That is the question!

Myelodysplastic syndromes (MDS) are a heterogeneous group of hemopathies that exhibit physical manifestations with clinical consequences of bone marrow failure and inherent risk of progression to acute myeloid leukemia. Iron overload (IO) is common in MDS due to chronic transfusion support and disease-related alterations in iron metabolism. IO has been conclusively associated with inferior outcomes among MDS patients. Despite lack of randomized trials showing a survival impact of iron chelation therapy (ICT), ICT is recommended by experts and guidelines for select MDS patients with IO and is often used. The availability of effective oral ICT agents has reignited the controversy regarding ICT use in patients with MDS and IO. Here we summarize the studies evaluating the value of ICT in MDS and suggest a practical approach for use of these therapies. We also highlight controversies regarding use of ICT in MDS and discuss some ongoing efforts to answer these questions.     

Quaternary dynamics and plasticity underlie small heat shock protein chaperone function

Small Heat Shock Proteins (sHSPs) are a diverse family of molecular chaperones that prevent protein aggregation by binding clients destabilized during cellular stress. Here we probe the architecture and dynamics of complexes formed between an oligomeric sHSP and client by employing unique mass spectrometry strategies. We observe over 300 different stoichiometries of interaction, demonstrating that an ensemble of structures underlies the protection these chaperones confer to unfolding clients. This astonishing heterogeneity not only makes the system quite distinct in behavior to ATP-dependent chaperones, but also renders it intractable by conventional structural biology approaches. We find that thermally regulated quaternary dynamics of the sHSP establish and maintain the plasticity of the system. This extends the paradigm that intrinsic dynamics are crucial to protein function to include equilibrium fluctuations in quaternary structure, and suggests they are integral to the sHSPs’ role in the cellular protein homeostasis network.     

A retinoic acid receptor β agonist (CD2019) overcomes inhibition of axonal outgrowth via phosphoinositide 3-kinase signalling in the injured adult spinal cord

After spinal cord injury in the adult mammal, axons do not normally regrow and this commonly leads to paralysis. Retinoic acid (RA) can stimulate neurite outgrowth in vitro of both the embryonic central and peripheral nervous system, via activation of the retinoic acid receptor (RAR) β2. We show here that regions of the adult CNS, including the cerebellum and cerebral cortex, express RARβ2. We show that when cerebellar neurons are grown in the presence of myelin-associated glycoprotein (MAG) which inhibits neurite outgrowth, RARβ can be activated in a dose dependent manner by a RARβ agonist (CD2019) and neurite outgrowth can occur via phosphoinositide 3-kinase (PI3K) signalling. In a model of spinal cord injury CD2019 also acts through PI3K signalling to induce axonal outgrowth of descending corticospinal fibres and promote functional recovery. Our data suggest that RARβ agonists may be of therapeutic potential for human spinal cord injuries.