Targeting intrinsic apoptosis and other forms of cell death by BH3-mimetics in glioblastoma

Introduction: Novel approaches to treat malignant brain tumors are necessary since these neoplasms still display an unfavorable prognosis.

Areas covered: In this review, the authors summarize and analyze recent preclinical data that suggest that targeting intrinsic apoptosis may be a suitable strategy for the treatment of malignant gliomas. They focus on the anti-apoptotic Bcl-2 family members of proteins and the recent drug developments in that field with a special focus on BH3-mimetics. With the discovery of BH3-mimetics that interfere with anti-apoptotic Bcl-2 family members in the low nanomolar range significant excitement has been generated towards these class of inhibitors, such as ABT-737, ABT-263 and the most recent successor, ABT-199 which is most advanced with respect to clinical application. The authors discuss the more recent selective inhibitors of Bcl-xL and Mcl-1. Concerning Mcl-1, these novel classes of inhibitors have the potential to impact malignant gliomas since these tumors reveal increased levels of Mcl-1.

Expert opinion: The recent development of certain small molecules raises significant hope that intrinsic apoptosis might soon be efficiently targetable for malignancies of the central nervous system. That being said, additional studies are necessary to determine which of the BH3-mimetics might be most suitable.     

Distribution and immunohistochemical localization of GDNF protein in selected neural and non-neural tissues of rats during development and changes in unilateral 6-hydroxydopamine lesions

The tissue distribution of glial cell line-derived neurotrophic factor (GDNF) during development and changes in GDNF levels by unilateral 6-hydroxydopamine lesions were investigated in rats using a newly established enzyme immunoassay system and by immunohistochemistry. The detection limit of the assay was 0.3 pg/0.2 ml and the system recognized glycosylated mature GDNF. Concentrations of GDNF were relatively high in the kidney and testis during the embryonic and neonatal periods, respectively, and decreased with age. In the striatum, hippocampus and brain stem, GDNF reached a maximal level at around postnatal day 14. However, brain levels were generally lower than those in non-neural tissues. In the CNS, GDNF immunoreactivity was observed in striatal neurons, pyramidal neurons in the hippocampus and the Vth layer of the cortex, large neurons in the diagonal band and brain stem, and spinal motor neurons. It was also evident in several non-neural, tissue-specific cells, such as cells in the renal collecting ducts and distal tubules, and testicular Sertoli cells. Destruction of nigral dopaminergic neurons by 6-hydroxydopamine enhanced the levels of striatal GDNF protein, with apparent involvement of astrocytes. These results suggest that GDNF is normally synthesized in neurons, but may also be produced by astroglial cells in damaged brains.     

A study of psycho-pathology and treatment of children with phagophobia

Phagophobia is a disorder characterized by a conditioned excessive fear of eating and is initiated by an event such as vomiting or choking. During childhood, vomiting often occurs as a result of infection or overeating, and painful experiences bring about maladaptive eating behavior like food refusal. There have been few reports of phagophobia, and patients have sometimes been misdiagnosed with anorexia nervosa (AN). The objective of this study was to elucidate the psycho-pathology and current treatment of patients with phagophobia by analyzing case studies. We describe 6 cases with phagophobia. Patients with strong obsessions were refractory to treatment, indicating that evaluation of premorbid personality is crucial to the prognosis. It is important to classify this disorder according to psycho-pathology into "post-traumatic type" and "gain-from-illness type" to make a treatment plan. A solution focused approach is also effective for patients and their family. Paying close attention to these conditions and to the diagnostic concept referred as "hagophobia" is useful in achieving these aims.     

Activation of granulocytes by direct interaction with dendritic cells

Granulocytes from human peripheral blood were co-cultured with conventional dendritic cells (cDC) or plasmacytoid DCs (pDC) to examine the effects of DCs on the activation or function of granulocytes. After co-culture of granulocytes with DCs, expression of the activation markers of granulocytes (CD63 and CD64) was up-regulated, and increased expression of CD50, the activation marker and ligand for CD209 (DC-SIGN) was also observed. The interaction of granulocytes with DCs was visualized as the cluster where DCs, especially cDCs, were surrounded by granulocytes to form a 'rosette'. After co-culture of granulocytes with cDCs, the secretion of elastase from granulocytes was enhanced significantly when examined cytohistochemically and by enzyme-linked immunosorbent assay. An increase in myeloperoxidase (another activation index of granulocytes) was also observed after co-culture with DCs. These findings suggest the functional and phenotypical activation of granulocytes by interaction with DCs. Furthermore, we examined the involvement of adhesion molecules in the granulocyte-DC interaction, and found that CD209 participates to some extent in this interaction.     

Endovascular Treatment of Aneurysmal Subarachnoid Hemorrhage in Japanese Registry of Neuroendovascular Therapy (JR-NET) 1 and 2

To distinguish the characteristics of ruptured cerebral aneurysm that are suitable for endovascular treatment from those that are not, we evaluated factors that influenced the results of aneurysm embolization in patients with ruptured cerebral aneurysm, based on data from the Japanese Registry of Neuroendovascular Therapy (JR-NET) 1 and 2. The multivariate analysis revealed that young patients, patients with low modified Rankin Scale (mRS) scores before onset, and patients with low World Federation of Neurosurgical Societies (WFNS) grades had good outcome. Compared to proximal internal carotid artery (ICA) aneurysms, the odds ratio of middle cerebral artery (MCA) aneurysms was 1.67, indicating poorer outcome for MCA aneurysms, and patients with small, wide-neck cerebral aneurysms had poor outcome. Patients treated after 15 days had better outcome than during other periods. The timing of treatment, however, did not influence the outcome in patients treated within 14 days. The outcome was poorer when the responsible doctor for the treatment was a specialist or a non-specialist than a supervisory doctor. The outcome of patients treated with bare platinum coils, and three dimensional (3D) rotational angiography was better, and the outcome of patients who completed treatment with body filling was poorer than in patients with complete occlusion. Perioperative hemorrhagic complications, all ischemic complications, and rebleeding occurred in 4.5%, 6.4%, and 1.4% of patients, respectively. All these complications had poor outcome factors on day 30, with odds ratios of 2.72, 2.96, and 25.49, respectively. We must be fully aware of these risk factors and determine indications for the treatment when endovascular treatment is performed as the treatment of choice for ruptured cerebral aneurysm.     

The latest wire technique for chronic total occlusion.

If patency is restored after chronic total occlusion (CTO), it can be maintained over the long term by implanting drug-eluting stents. The cause of unsuccessful percutaneous coronary intervention is usually failure of the wire to cross the site of CTO. The objective of this article is to describe the latest wire techniques for CTO. As for wire selection, CTO should generally be treated with hard-tipped spring wires, preferably Conquest Pro series (Asahi Intec). According to the penetrating strategy, the course of a blood vessel with CTO is established preoperatively and the wire is advanced based on the imaging data with minimum rotation (a torque of +/- 90 degrees or less). If the operator encounters divergence between the preoperative CTO image and the actual course of the coronary artery, the parallel wire technique should be used. With this method, a wire which enters the subintimal space is left there, and a second wire is inserted along it to find a new channel. When this technique is successful, the following findings are often noted: 1) the second wire crosses over the first one in the CTO; 2) the second wire shows more acute curve than the first wire; 3) the second wire penetrates the lesion from the outer curvature of the coronary artery and then is advanced along the same curvature of the vessel. Indeed, the second wire should be operated intentionally to achieve these findings so that the probability of success increases and the duration of the procedure is shortened.     

Development of takotsubo cardiomyopathy with severe pulmonary edema before a cesarean section

Takotsubo cardiomyopathy is an acute syndrome involving apical ballooning and consequent dysfunction of the left ventricle. Most cases of left ventricular dysfunction resolve within 1 month. We present the case of a 40-year-old woman who developed severe heart failure caused by takotsubo cardiomyopathy with severe left ventricular dysfunction during the perinatal period. Because of the presence of multiple myomas, she was scheduled to undergo a cesarean section under general anesthesia. However, after induction of general anesthesia, she had to be awakened because of the presence of a difficult airway. Because she exhibited insufficient oxygenation, she was transferred to the emergency center. Upon hospital admission, she expectorated large amounts of pink sputum, indicating severe pulmonary edema. Cesarean section was performed immediately. Echocardiography revealed severe left ventricular dysfunction. Full recovery of cardiac function required almost 1 month, after which she was discharged from the hospital without further complications. This is the first reported case of takotsubo cardiomyopathy induced by a failed intubation during a scheduled cesarean section. Takotsubo cardiomyopathy usually shows a good prognosis, but if this myopathy develops during the perinatal period, it can worsen because of excessive preload following the termination of fetoplacental circulation.     

Continuous fever-range heat stress induces thermotolerance in odontoblast-leneage cells

Objective

Heat shock during restorative procedures can trigger damage to the pulpodentin complex. While severe heat shock has toxic effects, fever-range heat stress exerts beneficial effects on several cells and tissues. In this study, we examined whether continuous fever-range heat stress (CFHS) has beneficial effects on thermotolerance in the rat clonal dental pulp cell line with odontoblastic properties, KN-3.

Methods

KN-3 cells were cultured at 41 °C for various periods, and the expression level of several proteins was assessed by Western blot analysis. After pre-heat-treatment at 41 °C for various periods, KN-3 cells were exposed to lethal severe heat shock (LSHS) at 49 °C for 10 min, and cell viability was examined using the MTS assay. Additionally, the expression level of odontoblast differentiation makers in surviving cells was examined by Western blot analysis.

Results

CFHS increased the expression levels of several heat shock proteins (HSPs) in KN-3 cells, and induced transient cell cycle arrest. KN-3 cells, not pre-heated or exposed to CFHS for 1 or 3 h, died after exposure to LSHS. In contrast, KN-3 cells exposed to CFHS for 12 h were transiently lower on day 1, but increased on day 3 after LSHS. The surviving cells expressed odontoblast differentiation markers, dentine sialoprotein and dentine matrix protein-1. These results suggest that CFHS for 12 h improves tolerance to LSHS by inducing HSPs expression and cell cycle arrest in KN-3 cells.

Conclusions

The appropriate pretreatment with continuous fever-range heat stress can provide protection against lethal heat shock in KN-3 cells.     

Mediastinal Malignant Melanoma Markedly Shrinking in Response to Nivolumab

Primary malignant melanoma (MM) of the mediastinum is rare, and there is a lack of consensus regarding the preferred treatment because non-cutaneous MM demonstrates an inferior response to systemic therapy. Herein, we describe the case of a 73-year-old man with MM of the anterior mediastinum with multiple liver metastases. Even though the size of lesions increased rapidly following diagnosis, nivolumab monotherapy caused remarkable tumor shrinkage. This is the first report of mediastinal MM showing a significant response to nivolumab. We, therefore, suggest that immunotherapy may be one of the treatment options for primary mediastinal MM.