The 1.5 GHz Electromagnetic Near-field Used for Cellular Phones Does Not Promote Rat Liver Carcinogenesis in a Medium-term Liver Bioassay

We have recently established that local exposure to a 929.2 MHz electromagnetic near-field, used for cellular phones, does not promote rat liver carcinogenesis in a medium-term bioassay system. In the present study, a 1.439 GHz electromagnetic near-field (EMF), another microwave band employed for cellular phones in Japan, was similarly investigated. Time division multiple access (TDMA) signals for the Personal Digital Cellular (PDC) Japanese cellular telephone standard system were directed to rats through a quarter-wavelength monopole antenna. Numerical dosimetry showed that the peak SARs within the liver were 1.91–0.937 W/kg, while the whole-body average specific absorption rates (SARs) were 0.680–0.453 W/kg, when the time-averaged antenna radiation power was 0.33 W. Exposure was for 90 min a day, 5 days a week, over 6 weeks, to male F344 rats given a single dose of diethylnitrosamine (200 mg/kg, i.p.) 2 weeks previously. At week 3, all rats were subjected to a two-thirds partial hepatectomy. At week 8, the experiment was terminated and the animals were killed. Carcinogenic potential was scored by comparing the numbers and areas of the induced glutathione S-transferase placental form (GST-P)-positive foci in the livers of exposed (48) and sham-exposed rats (48). Despite increased serum levels of corticosterone, adrenocorticotropic hormone (ACTH) and melatonin, the numbers and the areas of GST-P-positive foci were not significantly altered by the exposure. These findings clearly indicated that local body exposure to a 1.439 GHz EMF, as in the case of a 929.2 MHz field, has no promoting effect on rat liver carcinogenesis in the present model.     

Association of Loss of Heterozygosity at the p53 Locus with Chemoresistance in Osteosarcomas

Although the osteosarcoma is considered to be among the most chemosensitive malignancies and preoperative chemotherapy is commonly applied, an appreciable proportion of cases are in fact quite insensitive. Predictive markers for chemosensitivity are therefore desirable in order to develop effective treatment strategies. Thirty-two cases of conventional osteosarcomas treated at the Cancer Institute Hospital, Tokyo, were analyzed. The sensitivity to preoperative chemotherapy was investigated with reference to loss of heterozygosity (LOH) at the 17p13 ( p 53) and 13q14 ( Rb ) loci and expression of the cell-cycle associated proteins, p53, Rb, p21/Waf-1, mdm-2 and Ki-67, as detected immunohistochemically. LOH was detected by analyzing polymerase chain reaction products at marker microsatellite loci. The efficacy of chemotherapy was evaluated both radiologically and histologically. LOH at p 53 or Rb loci was seen in 54% (13/24) and 58% (14/24) of cases, respectively. Only 15% of osteosarcomas with LOH at the p 53 locus were sensitive to preoperative chemotherapy, as compared to 64% of tumors without such loss ( P <0.05). A similar but much less distinct tendency was observed with LOH at the Rb locus. No relationship was evident between chemosensitivity and immunohistochemical staining patterns for p53, Rb, p21/Waf-1, mdm-2 or Ki-67. The results suggest that p 53 gene deletion, but not the other parameters investigated, may be useful for predicting chemoresistance of osteosarcomas.     

Hyperlipidemia as a risk factor for Trousseau syndrome-related cerebral infarction in patients with advanced gastrointestinal cancer

Trousseau syndrome-related cerebral infarction rarely occurs during chemotherapy in patients with gastrointestinal (GI) cancer, and its clinical features remain unclear. The present study aimed to examine the clinical features of Trousseau syndrome-related cerebral infarction developed during chemotherapy for GI cancer. The present retrospective cohort study consecutively enrolled 878 patients with unresectable GI cancer who received chemotherapy at the Multidisciplinary Treatment Cancer Center, Kurume University Hospital (Kurume, Japan) between April 2014 and March 2020. Patients with colorectal cancer (n=308) were the most common, followed by those with pancreatic (n=242), gastric (n=222) and biliary tract (n=59) cancer, neuroendocrine tumors (n=34) and duodenal cancer (n=11). Among the 878 patients, Trousseau syndrome-related cerebral infarction occurred in 8 (0.9%) patients with a median age of 70.5 years (range, 58–75 years), and 50% of the patients were male (4/8). In total, 3 patients had gastric cancer, 3 had pancreatic cancer and 2 had biliary tract cancer. A greater percentage of patients with Trousseau syndrome-related cerebral infarction had hyperlipidemia (38.0%) than those without (8.2%; P=0.005). Hyperlipidemia was a risk factor for occurrence of Trousseau syndrome-related cerebral infarction with an odds ratio of 7.009 (95% confidence interval, 1.785-27.513). Trousseau syndrome-related cerebral infarction developed during GI chemotherapy was rare and hyperlipidemia may predict its onset.     

A novel hepatic-targeting system for therapeutic cytokines that delivers to the hepatic asialoglycoprotein receptor,but avoids receptor-mediated endocytosis

Purpose. To demonstrate the utilities of a synthetic low-affinity ligand ((Gal)₃) for the asialoglycoprotein receptor (ASGP-R) as a hepatic targeting device for therapeutic cytokines. Methods. The site-specific incorporation of (Gal)₃ or a typical high-affinity ligand (GalNAc)₃ into IL-2 was catalyzed by microbial transglutaminase. The anti-tumor activities, pharmacokinetic profiles and receptor-mediated endocytosis in hepatocytes of the ligand-IL-2 conjugates were examined in mouse. Results. The (Gal)₃ has approximately 50 times lower affinity to ASGP-R than (GalNAc)₃. Nevertheless, the antitumor effects were in the order of (Gal)₃—IL-2 > unmodified IL-2 > (GalNAc)₃—IL-2. The systemic elimination and the hepatic uptake of (GalNAc)₃—IL-2 were more rapid than (Gal)₃—IL-2. The ratio of the rate constant representing dissociation from the cell-surface receptor (k_off) to that representing endocytosis of the ligand (k_int) was greater for (Gal)₃—IL-2 than (GalNAc)₃—IL-2, suggesting that (Gal)₃—IL-2 preferably avoids internalization due to its lower affinity to the receptor. The simulation studies demonstrated that (Gal)₃—IL-2 was present in the hepatic extracellular space for a longer period than (GalNAc)₃ IL-2. Conclusions. The (Gal)₃ ligand increases the therapeutic efficacy of IL-2 by enhancing its exposure to the cell-surface. The k_off/k_int affects the targeting efficacy of the conjugates to ASGP-R.     

Double stapling method for closure of intraoperative alveolar air leakage adjacent to the staple line: a randomized experimental study on ex vivo porcine lungs

BackgroundAlveolar air leakage from a pleural defect around the staple line is one of the complications after wedge resection of the lung. An intraoperative closure of the pleural defect by suturing can cause additional pleural rupture due to tension of the pleura adjacent to staple lines. Therefore, we have introduced a novel closure method for pleural defect adjacent to the staple line, named the double stapling method. This study compared the efficacy of two closure methods; the double stapling method and conventional suturing method with pledgets using ex vivo porcine lungs.MethodsThe double stapling method involves closing the pleural defect by suturing the two parallel staple lines at both sides of the pleural defect. This method was developed to distribute the pleural tension around the needle holes of suturing. As a model of pleural defect adjacent to the staple line after wedge resection, wedge resection of the caudal lobe of left porcine lungs was performed, and a superficial square pleural defect (10 mm × 10 mm) adjacent to the staple line was made by scalpel. The defect was closed using the following two methods: (I) suturing with pledgets (n=10); and (II) double stapling method (n=10). The lobe was inflated in water at an airway pressure of 20, 25, and 30 cmH₂O; closure success or failure was judged by the absence or presence of air leakage.ResultsThe closure success was confirmed in 2 (20%) out of 10 cases in the suturing with pledgets group and 9 (90%) out of 10 in the double stapling method group (P=0.007). In 4 out of 10 cases in the suturing with pledgets group, new pleural clefts longer than 3 mm were created around the needle holes of suturing.ConclusionsEx vivo experiments have suggested the superiority of the double stapling method for the intraoperative closure of alveolar air leakage adjacent to the staple line after wedge resection, compared to conventional suturing with the pledget method.     

Anti-SARS CoV-2 IgG in COVID-19 Patients with Hematological Diseases: A Single-center,Retrospective Study in Japan

Objective Coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread globally. Although the relationship between anti-SARS-CoV-2 immunoglobulin G (IgG) antibodies and COVID-19 severity has been reported, information is lacking regarding the seropositivity of patients with particular types of diseases, including hematological diseases. Methods In this single-center, retrospective study, we compared SARS-CoV-2 IgG positivity between patients with hematological diseases and those with non-hematological diseases. Results In total, 77 adult COVID-19 patients were enrolled. Of these, 30 had hematological disorders, and 47 had non-hematological disorders. The IgG antibody against the receptor-binding domain of the spike protein was detected less frequently in patients with hematological diseases (60.0%) than in those with non-hematological diseases (91.5%; p=0.029). Rituximab use was significantly associated with seronegativity (p=0.010). Conclusion Patients with hematological diseases are less likely to develop anti-SARS-CoV-2 antibodies than those with non-hematological diseases, which may explain the poor outcomes of COVID-19 patients in this high-risk group.     

Quantitative Assay of Epidermal Growth Factor Receptor in Human Squamous Cell Carcinomas of the Oral Region by an Avidin-Biotin Method

A quantitative assay method for epidermal growth factor receptors (EGFRs) of human tumor tissues was established, based on enzyme-labeled avidin-biotin (LAB) interaction with anti-human EGFR monoclonal antibody 52SIgG. A standard calibration curve for EGFR estimation in human tumor tissues was obtained with A431#8 cells cloned from A431 human epidermoid carcinoma cell line. The coefficient of variance for the standard curve was below 35% in the application to tumor tissues from nude mice implanted with human tumor cell lines. The minimum tissue amount required for the quantitative assay was around 0.1 g (wet weight). Using the LAB method, the correlation between the level of EGFR number and tumor malignancy was examined for 14 human squamous cell carcinomas (SCCs) from the oral region. Seven of the SCCs showed a more than two-fold higher EGFR number compared to normal gingival tissues. Three highly aggressive carcinomas with poor prognosis possessed five to ten times higher levels of EGFR number than normal tissues. The elevated EGFR level in the SCCs seems to correlate to increasing tumor size and the stage of SCCs as clinically classified according to the 1987 UICC TNM system.     

Synthesis and photophysical properties of photostable 1,8-naphthalimide dyes incorporating benzotriazole-based UV absorbers

We developed a series of blue-emitting 1,8-naphthalimide dyes covalently attached to 2-(2-hydroxyphenyl)-2H-benzotriazoles that retard photodegradation of the fluorophore. The dyes displayed weaker fluorescence emissions than the parent 1.8-naphthalimide. Quantum chemical calculations suggested that the decreased fluorescence was caused by the nonradiative deactivation promoted through the excited state intramolecular proton transfer (ESIPT) in benzotriazole components. The dyes'' phosphorescences in a degassed solution at 77 K were more efficient than that of the parent 1.8-naphthalimide, indicating a possible deactivation pathway through intersystem crossing. PMMA films doped with these dyes showed higher resistance against photoaging than the film doped with an equimolar mixture of constituent 1.8-naphthalimide and the benzotriazole derivatives. Thus, the covalently linked benzotriazole units slow fluorophore degradation not only by preferential absorption of harmful UV light, which is found in the film with a simple mixture of two components, but also by the nonradiative deactivation involved in benzotriazole units.

Highly photostable blue fluorescence dyes were developed by hybridization of 1,8-naphthalimides with benzotriazole-based UV absorbers enabling a non-radiative energy dissipation process of excited-state intramolecular proton transfer (ESIPT).     

Effects of Five Amino Acids (Serine,Alanine, Glutamate,Aspartate, and Tyrosine) on Mental Health in Healthy Office Workers: A Randomized,Double-Blind,Placebo-Controlled Exploratory Trial

Background: The importance of maintaining good mental health with overall well-being has recently drawn attention from various spheres of academics and the working population. Amino acid intake has been reported to reduce depression symptoms and other mental health problems. However, the effectiveness of amino acid intake (i.e., single or combined) remains unknown. In this study, we assessed a combination of five amino acids (serine, alanine, glutamate, aspartate, and tyrosine; SAGAT) reported to regulate mental health. Methods: A randomized, double-blind, placebo-controlled exploratory trial was conducted. Participants, aged between 20 and 65 years with fatigue sensation, were randomized to receive either SAGAT or the placebo and ingested them for four weeks. A transient mental work was loaded at day 0 and after four weeks of intervention. As the primary outcomes, the fatigue sensation was assessed. The mood status, cognitive function, work efficiency, and blood marker were also measured as secondary outcomes. Results: The number of participants analyzed for the efficacy evaluation were 20 in SAGAT and 22 in the placebo. There were no significant differences in the primary outcomes. However, as the secondary outcomes, the SAGAT group showed a significant improvement in motivation and cognitive function in the recovery period after mental work loaded in a four-week intervention compared to the placebo. Conclusion: The current findings suggest that SAGAT contributes to maintaining proper motivation and cognitive function. Clinical Trial Registration: University Hospital Medical Information Network Clinical Trial Registry (ID: UMIN 000041221).