Contribution of acidic extracellular microenvironment of cancer-colonized bone to bone pain

Solid and hematologic cancer colonized bone produces a number of pathologies. One of the most common complications is bone pain. Cancer-associated bone pain (CABP) is a major cause of increased morbidity and diminishes the quality of life and affects survival. Current treatments do not satisfactorily control CABP and can elicit adverse effects. Thus, new therapeutic interventions are needed to manage CABP. However, the mechanisms responsible for CABP are poorly understood. The observation that specific osteoclast inhibitors can reduce CABP in patients indicates a critical role of osteoclasts in the pathophysiology of CABP. Osteoclasts create an acidic extracellular microenvironment by secretion of protons via vacuolar proton pumps during bone resorption. In addition, bone-colonized cancer cells also release protons and lactate via plasma membrane pH regulators to avoid intracellular acidification resulting from increased aerobic glycolysis known as the Warburg effect. Since acidosis is algogenic for sensory neurons and bone is densely innervated by sensory neurons that express acid-sensing nociceptors, the acidic bone microenvironments can evoke CABP. Understanding of the mechanism by which the acidic extracellular microenvironment is created in cancer-colonized bone and the expression and function of the acid-sensing nociceptors are regulated should facilitate the development of novel approaches for management of CABP. Here, the contribution of the acidic microenvironment created in cancer-colonized bone to elicitation of CABP and potential therapeutic implications of blocking the development and recognition of acidic microenvironment will be described. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers

Identification of multiple actin-binding sites in cofilin-phosphatase Slingshot-1L

AbstractSlingshot-1L (SSH1L) is a phosphatase that specifically dephosphorylates and activates cofilin, an actin-severing and -depolymerizing protein. SSH1L binds to and is activated by F-actin in vitro, and co-localizes with F-actin in cultured cells. We examined the F-actin-binding activity, F-actin-mediated phosphatase activation, and subcellular distribution of various mutants of SSH1L. We identified three sites involved in F-actin binding of SSH1L: Trp-458 close to the C-terminus of the phosphatase domain, an LHK motif in the N-terminal region, and an LKR motif in the C-terminal region. These sites play unique roles in the control of subcellular localization and F-actin-mediated activation of SSH1L

Purification and complete amino acid sequence of canine pancreatic secretory trypsin inhibitor

AbstractPancreatic secretory trypsin inhibitor (PSTI) was purified from canine pancreatic juice by HPLC. Canine PSTI inhibited bovine trypsin activity stoichiometrically and strongly with a dissociation constant of below 10−9 M. The amino acid sequence of canine PSTI was determined by conventional methods. It had one more amino acid residue at the amino-terminus than other mammalian PSTIs, i.e. human, porcine, bovine and ovine

Autophosphorylation at serine 166 regulates RIP kinase 1-mediated cell death and inflammation

Receptor interacting protein kinase 1 (RIPK1) regulates cell death and inflammatory responses downstream of TNFR1 and other receptors, and has been implicated in the pathogenesis of inflammatory and degenerative diseases. RIPK1 kinase activity induces apoptosis and necroptosis, however the mechanisms and phosphorylation events regulating RIPK1-dependent cell death signaling remain poorly understood. Here we show that RIPK1 autophosphorylation at serine 166 plays a critical role for the activation of RIPK1 kinase-dependent apoptosis and necroptosis. Moreover, we show that S166 phosphorylation is required for RIPK1 kinase-dependent pathogenesis of inflammatory pathologies in vivo in four relevant mouse models. Mechanistically, we provide evidence that trans autophosphorylation at S166 modulates RIPK1 kinase activation but is not by itself sufficient to induce cell death. These results show that S166 autophosphorylation licenses RIPK1 kinase activity to induce downstream cell death signaling and inflammation, suggesting that S166 phosphorylation can serve as a reliable biomarker for RIPK1 kinase-dependent pathologies

The Development of a New Setup for Video-assisted Thoracic Surgery

In order to accomplish video-assisted thoracic surgery (VATS) in a much easier and safer way, especially for assistant operators, we have developed a new display system for VATS. The original thoracoscope has been designed for this new system. The monitor is fixed at approximately 10 cm away from the surface of the chest wall just above the operative field. In using this procedure, the operator and assistants can see the patient and the monitor at the same time. According to this new idea, the previous problem in the area of hand–eye coordination and the three-dimensional understanding of this procedure can be improved compared to the image of the conventional thoracoscopy, because it is not necessary for the operator and assistants to look up at the monitors. When the thoracoscopy was placed in an adequate position to resect the target pathology, this new system led to good and easy handling of instruments, as it was with the standard thoracotomy

External iliac venous aneurysm in a pregnant woman: a case report

AbstractWe report an external iliac venous aneurysm in a young pregnant woman who was diagnosed incidentally by ultrasound scanning. The aneurysm was successfully treated by tangential aneurysmectomy and lateral venorrhaphy. Primary iliac venous aneurysm is a rare vascular abnormality. The clinical significance of the disease is unknown. However, embolism, rupture, and thrombosis might occur as they can occur with popliteal venous aneurysm. In fact, three of four reported patients with iliac venous aneurysms had a thromboembolic event. For those reasons, prophylactic treatment is indicated. This is the first patient with an iliac venous aneurysm to be diagnosed without complication

Expert consensus on hospitalization for assessment: a survey in Japan for a new forensic mental health system

<p>Abstract</p> <p>Background</p> <p>In Japan, hospitalization for the assessment of mentally disordered offenders under the Act on Medical Care and Treatment for the Persons Who Had Caused Serious Cases under the Condition of Insanity (the Medical Treatment and Supervision Act, or the MTS Act) has yet to be standardized.</p> <p>Methods</p> <p>We conducted a written survey that included a questionnaire regarding hospitalization for assessment; the questionnaire consisted of 335 options with 9 grades of validity for 60 clinical situations. The survey was mailed to 50 Japanese forensic mental health experts, and 42 responses were received.</p> <p>Results</p> <p>An expert consensus was established for 299 of the options. Regarding subjects requiring hospitalization for assessment, no consensus was reached on the indications for electroconvulsive therapy (ECT) or for confronting the offenders regarding their offensive behaviors.</p> <p>Conclusions</p> <p>The consensus regarding hospitalization for assessment and its associated problems were clarified. The consensus should be widely publicized among practitioners to ensure better management during the hospitalization of mentally disordered offenders for assessment.</p

Suzaku X-Ray Spectroscopy of a Peculiar Hot Star in the Galactic Center Region

We present the results of a Suzaku study of a bright point-like source in the 6.7 keV intensity map of the Galactic center region. We detected an intense FeXXV 6.7 keV line with an equivalent width of ~1 keV as well as emission lines of highly ionized Ar and Ca from a spectrum obtained by the X-ray Imaging Spectrometer. The overall spectrum is described very well by a heavily absorbed (~2x10^{23}cm^{-2}) thin thermal plasma model with a temperature of 3.8+/-0.6 keV and a luminosity of ~3x10^{34} erg s^{-1} (2.0--8.0 keV) at 8 kpc. The absorption, temperature, luminosity, and the 6.7 keV line intensity were confirmed with the archived XMM-Newton data. The source has a very red (J-Ks=8.2 mag) infrared spectral energy distribution (SED), which was fitted by a blackbody emission of ~1000 K attenuated by a visual extinction of ~31 mag. The high plasma temperature and the large X-ray luminosity are consistent with a wind-wind colliding Wolf-Rayet binary. The similarity of the SED to those of the eponymous Quintuplet cluster members suggests that the source is a WC-type source.Comment: Accepted for publication on PASJ Vol.60, SP-1, 200