Electrostatic Levitation Furnace for the ISS

JAXA (Japan Aerospace Exploration Agency) has just started the development of Electrostatic Levitation Furnace to be launched in 2014 for the ISS. This furnace can control the sample position with electrostatic force and heat it above 2000 degree Celsius using semiconductor laser from four different directions. The announcement of Opportunity will be issued soon for this furnace. In this paper, we will show the specifications of this furnace and also the development schedul

Prognostic factors for progression of visual field deterioration in patients with primary open-angle glaucoma

Regulatory T cells (Tregs) play an important role in the maintenance of self-tolerance and immune homeostasis. Interleukin-2 (IL-2) is critical for Treg expansion, activity and survival. Previous studies have demonstrated that low-dose IL-2 resulted in the selective expansion of Tregs and the clinical improvement of auto-immune disease. To examine the mechanisms whereby IL-2 affects Treg apoptosis through the intrinsic pathway, we used BH3 profiling, and quantitated mitochondrial apoptotic priming. This pattern suggests that Tregs were more primed than conventional CD4 T cells (Tcons) in a BCL2-dependent manner. Tregs expressed lower levels of BCL2 than Tcons. To examine the functional effects of IL-2, sorted Tregs and Tcons were cultured with different concentrations of IL-2. Low-dose IL-2 (10 IU/mL) lowered priming and increased BCL2 expression in Tregs. However, higher concentrations of IL-2 (>100 IU/mL) were required to increase BCL2 expression and decrease priming in Tcons. Apoptosis assays also revealed that low-dose IL-2 reduced susceptibility to apoptosis only in Tregs. ABT-199, a selective BCL2 inhibitor, enhanced the priming and apoptosis of both Tcells. IL-2 reversed the effects of ABT-199 for Tregs only. This provides further evidence that the inhibition of intrinsic pathway apoptosis mediated by IL-2 in Tregs is dependent on BCL2

Prognostic factors for progression of visual field deterioration in patients with primary open-angle glaucoma

Regulatory T cells (Tregs) play an important role in the maintenance of self-tolerance and immune homeostasis. Interleukin-2 (IL-2) is critical for Treg expansion, activity and survival. Previous studies have demonstrated that low-dose IL-2 resulted in the selective expansion of Tregs and the clinical improvement of auto-immune disease. To examine the mechanisms whereby IL-2 affects Treg apoptosis through the intrinsic pathway, we used BH3 profiling, and quantitated mitochondrial apoptotic priming. This pattern suggests that Tregs were more primed than conventional CD4 T cells (Tcons) in a BCL2-dependent manner. Tregs expressed lower levels of BCL2 than Tcons. To examine the functional effects of IL-2, sorted Tregs and Tcons were cultured with different concentrations of IL-2. Low-dose IL-2 (10 IU/mL) lowered priming and increased BCL2 expression in Tregs. However, higher concentrations of IL-2 (>100 IU/mL) were required to increase BCL2 expression and decrease priming in Tcons. Apoptosis assays also revealed that low-dose IL-2 reduced susceptibility to apoptosis only in Tregs. ABT-199, a selective BCL2 inhibitor, enhanced the priming and apoptosis of both Tcells. IL-2 reversed the effects of ABT-199 for Tregs only. This provides further evidence that the inhibition of intrinsic pathway apoptosis mediated by IL-2 in Tregs is dependent on BCL2

Isoform D of vascular endothelial growth factor in systemic capillary leak syndrome : a case report

Background: Systemic capillary leak syndrome is a rare condition characterized by episodic attacks of hypovolemia due to systemic capillary hyperpermeability, which results in profound hypotension and edema. Although the implication of vascular endothelial growth factor, angiopoietin-2, and C-X-C motif chemokine 10 has been suggested, the pathogenesis of systemic capillary leak syndrome remains unclear. In this report, we describe a case of systemic capillary leak syndrome in which serum isoform D of vascular endothelial growth factor was elevated. To the best of our knowledge, this is the first reported case of systemic capillary leak syndrome in which isoform D of vascular endothelial growth factor is suggested as the plausible biomarker. Case presentation: A 41-year-old Japanese man was transferred to our emergency department. He was hypotensive, tachycardic, and edematous over the trunk and all four limbs. He received aggressive intravenous fluid therapy and underwent fasciotomy of the right forearm to prevent muscle necrosis. A diagnosis of systemic capillary leak syndrome was suspected. The presence of serum monoclonal immunoglobulin G and κ light chain supported this diagnosis. Prevention of hypotensive crises was unsuccessfully attempted with theophylline, intravenous immunoglobulin, high-dose dexamethasone, bortezomib, melphalan, and prednisolone; however, the patient’s attacks dramatically disappeared after the introduction of thalidomide. The serum of the patient was stored soon after the onset of hypotensive crisis and analyzed to profile possible mediators responsible for the capillary leak. The concentration of vascular endothelial growth factor, angiopoietin-2, and C-X-C motif chemokine 10 were all within normal ranges. Meanwhile, we found that isoform D of vascular endothelial growth factor was elevated, which was normalized after the introduction of thalidomide. Conclusions: In our patient, isoform D of vascular endothelial growth factor (instead of vascular endothelial growth factor) may have been a causative factor of hypotensive crises, since isoform D contributes to vascular endothelial growth factor receptor-2 signaling, which is the major mediator of the permeability-enhancing effects of vascular endothelial growth factor. We suggest the measurement of isoform D of vascular endothelial growth factor in patients with systemic capillary leak syndrome in whose serum vascular endothelial growth factor is not elevated

Pemphigus vulgaris as an immune-related adverse event in recurrent metastatic esophageal squamous cell carcinoma treated with ipilimumab plus nivolumab: a case report and literature review

Ipilimumab plus nivolumab therapy is approved for patients with unresectable advanced esophageal squamous cell carcinoma (ESCC). Although a combination of immune checkpoint inhibitors (ICIs), compared to conventional chemotherapy, can improve overall survival in patients with advanced ESCC, this increases the incidence of immune-related adverse events (irAEs). Here, we describe an ESCC case that developed pemphigus vulgaris (PV), an extremely rare cutaneous irAE, during ipilimumab plus nivolumab treatment. The patient achieved a partial response to treatment. The PV was successfully managed after the cessation of ipilimumab and the use of a topical steroid. We should thus re-treat ESCC with nivolumab monotherapy. In the era of ICIs as standard cancer therapeutics, diagnostic criteria for blistering diseases need to be established to properly manage patients with cutaneous irAEs

Trastuzumab-Based Combination Chemotherapy in Patients with Human Epidermal Growth Factor Receptor-2-Positive Metastatic Carcinoma ex Pleomorphic Adenoma

Background: Carcinoma ex pleomorphic adenoma (CXPA) is a rare histologic subtype of lacrimal gland and submandibular gland cancer. Currently, there is no standard treatment for metastatic CXPA, although some case reports have explored the role of targeted agents in chemotherapy. A few histopathologic analyses have shown that some of these tumors overexpress human epidermal growth factor receptor-2 (HER2), suggesting a potential role for HER2-based therapy. We report here two cases of metastatic CXPA that were treated with trastuzumab-based chemotherapy (IRB approved) with rapid and significant responses. Case Report 1: A 66-year-old male was diagnosed as HER2-positive CXPA of the right lacrimal gland with multiple bone and lymph node metastases. Combination chemotherapy with trastuzumab (Tmab) and nanoparticle albumin-bound paclitaxel (nabPTX) was initiated. A rapid response was confirmed, and after seven cycles of treatment, CR(complete response) was achieved. Case Report 2: A 67-year-old female was diagnosed with HER2 positive CXPA of the right submandibular gland. Multiple pulmonary metastatic lesions were detected after surgery, and combination chemotherapy with Tmab and nab-PTX was initiated. A rapid partial response (PR) was confirmed, and she eventually became disease-free. Conclusion: In the absence of definitive clinical trials, which are unlikely to be performed due to the rarity of HER2-positive CXPA, therapeutic information must be obtained from case reports. Some reports, such as this one, have suggested a potential utility of trastuzumab-based chemotherapy

Successful Treatment of Hepatocellular Carcinoma with Transcatheter Arterial Chemoembolization followed by Radical Liver Transplantation in a Patient with Severe Liver Damage

Introduction: Liver transplantation for hepatocellular carcinoma (HCC) has been established as a curative therapy of underlying liver disease and cancer. However, the role of liver transplantation remains controversial for patients with HCC beyond Milan criteria. Case Presentation: A man in his 50s who was diagnosed as having two foci of HCC and advanced liver cirrhosis was referred to our hospital for further examination and treatment. Both foci of HCC were located in segment 8 of the liver and measured 39 and 9 mm. Endoscopy showed esophageal varices that had a high risk of bleeding. After endoscopic ligation of the esophageal varices, he underwent transcatheter arterial chemoembolization (TACE) for downstaging of the advanced HCCs. No further liver deterioration was observed after TACE, and HCC staging was successfully downstaged to within the Milan criteria. One hundred ten days after TACE, he underwent liver transplantation; at 2.5 years after transplantation, he remains alive without HCC recurrence. Discussion/Conclusion: There are only a few treatment options available for patients with advanced HCC and severe liver damage. Multidisciplinary treatment such as locoregional treatments and prophylaxis of variceal bleeding may result in tumor downstaging, enabling radical liver transplantation without further exacerbation of liver damage

The iron chelator deferasirox induces apoptosis by targeting oncogenic Pyk2/β-catenin signaling in human multiple myeloma

Deregulated iron metabolism underlies the pathogenesis of many human cancers. Recently, low expression of ferroportin, which is the only identified non-heme iron exporter, has been associated with significantly reduced overall survival in multiple myeloma (MM); however, the altered iron metabolism in MM biology remains unclear. In this study we demonstrated, by live cell imaging, that MM cells have increased intracellular iron levels as compared with normal cells. In experiments to test the effect of iron chelation on the growth of MM cells, we found that deferasirox (DFX), an oral iron chelator used to treat iron overload in clinical practice, inhibits MM cell growth both in vivo and in vitro. Mechanistically, DFX was found to induce apoptosis of MM cells via the inhibition of proline-rich tyrosine kinase 2 (Pyk2), which is known to promote tumor growth in MM. Inhibition of Pyk2 is caused by the suppression of reactive oxygen species, and leads to downregulation of the Wnt/β-catenin signaling pathway. Taken together, our findings indicate that high levels of intracellular iron, which might be due to low ferroportin expression, play a role in MM pathophysiology. Therefore, DFX may provide a therapeutic option for MM that is driven by deregulated iron homeostasis and/or Pyk2/Wnt signaling

Targeting Notch-1 positive acute leukemia cells by novel fucose-bound liposomes carrying daunorubicin

Complete remission by induction therapy in acute myelogenous leukemia (AML) can be achieved due to improvements in supportive and optimized therapy. However, more than 20% of patients will still need to undergo salvage therapy, and most will have a poor prognosis. Determining the specificity of drugs to leukemia cells is important since this will maximize the dose of chemotherapeutic agents that can be administered to AML patients. In turn, this would be expected to lead to reduced drug toxicity and its increased efficacy. We targeted Notch-1 positive AML cells utilizing fucose-bound liposomes, since activation of Notch-1 is required for O-fucosylation. Herein, we report that intravenously injected, L-fucose-bound liposomes containing daunorubicin can be successfully delivered to AML cells that express fucosylated antigens. This resulted in efficient tumor growth inhibition in tumor-bearing mice and decreased proliferation of AML patient-derived leukemia cells. Thus, biological targeting by fucose-bound liposomes that takes advantage of the intrinsic characteristics of AML cells could be a promising new strategy for Notch-1 positive-AML treatment