Solid‐type poorly differentiated adenocarcinoma of the stomach: Deficiency of mismatch repair and SWI/SNF complex

ARID1A, one of the subunits in SWI/SNF chromatin remodeling complex, is frequently mutated in gastric cancers with microsatellite instability (MSI). The most frequent MSI in solid‐type poorly differentiated adenocarcinoma (PDA) has been reported, but the SWI/SNF complex status in solid‐type PDA is still largely unknown. We retrospectively analyzed 54 cases of solid‐type PDA for the expressions of mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6), SWI/SNF complex subunits (ARID1A, INI1, BRG1, BRM, BAF155, and BAF170) and EBER, and mutations in KRAS and BRAF. We analyzed 40 cases of another histological type of gastric cancer as a control group. The solid‐type PDAs showed coexisting glandular components (76%), MMR deficiency (39%), and complete/partial loss of ARID1A (31%/7%), INI1 (4%/4%), BRG1 (48%/30%), BRM (33%/33%), BAF155 (13%/41%), and BAF170 (6%/2%), EBER positivity (4%), KRAS mutation (2%), and BRAF mutation (2%). Compared to the control group, MMR deficiency and losses of ARID1A, BRG1, BRM, and BAF155 were significantly frequent in solid‐type PDAs. Mismatch repair deficiency was associated with the losses of ARID1A, BRG1, and BAF155 in solid‐type PDAs. In the MMR‐deficient group, solid components showed significantly more frequent losses of ARID1A, BRG1, BRM, and BAF155 compared to glandular components (P = .0268, P = .0181, P = .0224, and P = .0071, respectively). In the MMR‐proficient group, solid components showed significantly more frequent loss of BRG1 compared to glandular components (P = .012). In conclusion, solid‐type PDAs showed frequent losses of MMR proteins and the SWI/SNF complex. We suggest that loss of the SWI/SNF complex could induce a morphological shift from differentiated‐type adenocarcinoma to solid‐type PDA.     

Clinical pharmacokinetics of oxaliplatin in a hemodialysis patient with advanced gastric cancer

We administered FOLFOX (oxaliplatin (L-OHP) plus infusional 5-fluorouracil (5-FU) and leucovorin) to an hemodialysis (HD) patient with advanced gastric cancer (AGC), and investigated pharmacokinetics (PKs) and dialyzability of L-OHP. The patient was a 54-year-old Japanese man with a diagnosis of inoperable AGC. FOLFOX was instituted 3?h prior to the start of a 4?h HD period with the L-OHP and 5-FU doses reduced by 50% for the first cycle, and 30% reduced dose was administered for the second cycle. We performed an analysis of the PKs of L-OHP during these two cycles. Volume of distribution and area under the curve of the 30% reduced L-OHP dose were 56.7?L and 30.0?μg·h/mL, respectively. A dose reduction of L-OHP by 30%?50% may be advisable for the initial administration, given the need for careful administration of chemotherapy in HD patients, with particular attention to the development of hematological toxicities and neuropathy.     

Preparation of an experimental mouse model lacking selenium-dependent glutathione peroxidase activities by feeding a selenium-deficient diet

Relatively young (4-week-old) selenium deficient (SeD) mice, which lack the activity of selenium-dependent glutathione peroxidase (GSH-Px) isomers, were prepared using torula yeast-based SeD diet. Mice were fed the torula yeast-based SeD diet and ultra-pure water. Several different timings for starting the SeD diet were assessed. The weekly time course of liver comprehensive GSH-Px activity after weaning was monitored. Protein expression levels of GPx1 and 4 in the liver were measured by Western blot analysis. Gene expression levels of GPx1, 2, 3, 4, and 7 in the liver were measured by quantitative real-time PCR. Apoptotic activity of thymocytes after hydrogen peroxide (H₂O₂) exposure was compared. Thirty-day survival rates after whole-body X-ray irradiation were estimated. Pre-birth or right-after-birth starting of the SeD diet in dams was unable to lead to creation of SeD mice due to neonatal death. This suggests that Se is necessary for normal birth and healthy growing of mouse pups. Starting the mother on the SeD diet from 2 weeks after giving birth (SeD-trial-2w group) resulted in a usable SeD mouse model. The liver GSH-Px activity of the SeD-trial-2w group was almost none from 4 week olds, but the mice survived for more than 63 weeks. Protein and gene expression of GPx1 was suppressed in the SeD-trial-2w group, but that of GPx4 was not. The thymocytes of the SeD-trial-2w group were sensitive to H₂O₂-induced apoptosis. The SeD-trial-2w group was sensitive to whole-body X-ray irradiation compared with control mice. The SeD-trial-2w model may be a useful animal model for H₂O₂/hydroperoxide-induced oxidative stress.     

Dietary Changes Impact the Gut Microbe Composition in Overweight and Obese Men with Prostate Cancer Undergoing Radical Prostatectomy

Background

Diet and obesity influence prostate cancer risk and progression–effects that may be mediated through the gut microbiome.

Condylar bone change and sagittal incisal and condylar paths during mandibular protrusive excursion

This study showed significant differences in sagittal condylar and incisal path angles during mandibular protrusive excursion, as well as flattening of the condylar path related to the existence and type of condylar bone change. Twenty-eight (28) patients with signs and symptoms of TMJ disorders were studied, using a six-degrees-of-freedom measuring device and helical CT. Sagittal incisal and condylar path angles at two mm and three mm condylar path lengths (CPL) were significantly shorter in the bilateral condylar bone change (BBC), compared to the no bone change (NBC) group. Also, NBC incremental sagittal condylar path angles from three to five mm CPL and NBC condylar path curvature at five mm CPL were both significantly larger than in BBC. Comparing types of bone change, incremental sagittal condylar path angles from three to five mm CPL was significantly less in osteophyte than in NBC or erosion groups. Condylar path curvature at five mm CPL was also significantly less in osteophyte than in NBC.     

Hemodynamic Changes by Drug Interaction of Adrenaline With Chlorpromazine

Adrenaline (epinephrine) is included in dental local anesthesia for the purpose of vasoconstriction. In Japan, adrenaline is contraindicated for use in patients receiving antipsychotic therapy, because the combination of adrenaline and an antipsychotic is considered to cause severe hypotension; however, there is insufficient evidence supporting this claim. The purpose of the present study was to clarify the changes in hemodynamics caused by drug interaction between adrenaline and an antipsychotic and to evaluate the safety of the combined use of adrenaline and an antipsychotic in an animal study. Male Sprague-Dawley rats were anesthetized with sodium pentobarbital. A catheter was inserted into the femoral artery to measure blood pressure and pulse rate. Rats were pretreated by intraperitoneal injection of chlorpromazine or chlorpromazine and propranolol, and after 20 minutes, saline or 1 of 3 different doses of adrenaline was administered by intraperitoneal injection. Changes in the ratio of mean arterial blood pressure and pulse rate were measured after the injection of adrenaline. Significant hypotension and tachycardia were observed after the injection of adrenaline in the chlorpromazine-pretreated rats. These effects were in a dose-dependent manner, and 100 μg/kg adrenaline induced significant hemodynamic changes. Furthermore, in the chlorpromazine and propranolol–pretreated rats, modest hypertension was induced by adrenaline, but hypotension and tachycardia were not significantly shown. Hypotension was caused by a drug interaction between adrenaline and chlorpromazine through the activation of the β-adrenergic receptor and showed a dose-dependent effect. Low-dose adrenaline similar to what might be used in human dental treatment did not result in a significant homodynamic change.Key Words: Local anesthesia, Drug interaction, Adrenaline, Epinephrine, AntipsychoticsVasoconstrictors are included in local anesthetics to increase the duration of anesthesia, to prevent local anesthesia systemic toxicity, and to promote hemostasis in the local operative field.¹ Adrenaline (epinephrine) is the most common vasoconstrictor that is added to local anesthetics, and lidocaine and articaine with adrenaline are the most widely used local anesthetics for dental treatment. However, adrenaline has drug interactions with some medicines. It is widely believed that the combination of adrenaline with an antipsychotic can cause hypotension because antipsychotics have α-adrenergic blocker effects that can result in decreased peripheral resistance, and adrenaline has been shown to have significant β2-adrenergic mediated vasodilatory effects that also can cause hypotension. Therefore, the combination of adrenaline and an antipsychotic is contraindicated in Japan for fear of causing significant hypotension. However, there is insufficient evidence supporting this claim, and, in clinical settings, there are many situations in which the use of local anesthetics with adrenaline is appropriate for dental treatment of patients receiving antipsychotic therapy. Thus, the purpose of the present study was to clarify the changes in hemodynamics caused by a drug interaction between adrenaline and an antipsychotic and to evaluate the safety of the combined use of adrenaline with an antipsychotic in an animal study.     

Therapeutic potential of transgenic mesenchymal stem cells engineered to mediate anti–high mobility group box 1 activity: targeting of colon cancer

Background

Mesenchymal stem cells (MSCs) are being developed as a new clinically relevant stem cell type to be recruited into and to repair injured tissue. A number of studies have focused on the therapeutic potential of MSCs by virtue of their immunomodulatory properties. Systemically administered MSCs can also migrate to sites of malignancies. Because of this latter phenomenon, we transfected human MSCs to secrete anti–high mobility group box (HMGB) 1 proteins. They were then injected into mice bearing human colon cancer to evaluate their efficacy as an antineoplastic agent.

Materials and methods

The ABOX gene was used in this model, which encodes part of the HMGB1 protein and acts as an HMGB1 antagonist. It was cotransduced by electroporation with a FLAG-tag to visualize the secreted ABOX protein, levels of which in supernatants from cultured transfected MSCs were quantified by immunofluorescence imaging using an anti-FLAG antibody. Antiangiogenic effects were evaluated in vitro using a novel optical assay device for the quantitative measurement of cellular chemotaxis assessing the velocity and direction of endothelial cell movement stimulated by supernatant from tumor cells. We found that ABOX proteins released from transfected MSCs suppressed migration in this assay. Finally, MSCs were injected subcutaneously into Nonobese diabetic/severe combined immunodeficiency mice bearing human colon cancer from a cell line, which secreted large amounts of HMGB1. Ten days after MSC injection, mice were sacrificed and tumors evaluated by immunohistochemistry.

Results

From 12 ho through 7 d after gene transfection, ABOX proteins secreted from MSCs could be detected by immunofluorescence and enzyme-linked immunosorbent assay. Quantitative measurement of cellular chemotaxis demonstrated that ABOX proteins secreted from transfected MSCs decreased the velocity and interfered with the direction of movement of vascular endothelial cells. Moreover, in an in vivo human colon cancer xenograft model, injection of anti-HMGB1–transfected MSCs resulted in a decreased tumor volume due to the antiangiogenic properties of the secreted ABOX proteins.

Conclusions

MSC modified to secrete HMGB1 antagonist proteins have therapeutic antineoplastic potential. These findings may contribute to future novel targeting strategies using autologous bone marrow–derived cells as gene delivery vectors.