Herein, we evaluate the photostability of pranoprofen (PP) tablets (NIFLAN® 75 mg), its powdered and suspended forms. PP is a member of the 2-arylpropionic acid family of NSAIDs. The content of the ...active compound was monitored by high-performance liquid chromatography (HPLC) using an ODS column with ultraviolet light (UV) detector. The residual amount of PP in the powder was 86.5%, which was comparable to that of in the suspension (85.4%) after UV irradiation for 24 hr. Further UV irradiation (total irradiation time of 7 days) resulted in the significant photodegradation of PP in the suspension (residual amount: 55.5%), compared to that of 1 day irradiation. However, the residual amount of PP in the powder was 78.6% after 7 days irradiation as the same to that of 1 day irradiation. To identify the chemical structure of five photoproducts generated from the UV-irradiated PP dosage forms, electrospray ionization liquid chromatography mass spectrometry (ESI-LC/MS/MS) analysis was performed. From these results, photodegradation of PP was observed through changing dosage forms. This is the first report evaluating the generation of PP photoproducts induced by the UV irradiation in the formulation.
Osteosarcoma is the most malignant type of bone tumor. Patients with osteosarcoma metastases have a poorer prognosis than those without metastases. Thus, the prognosis of osteosarcoma patients with ...metastases must be improved.
The present study investigated the inhibitory effects of 6-hydroxythiobinupharidine isolated from Nuphar pumilum on migration of LM8 murine osteosarcoma cells by a migration assay and also examined the expression of proteins related to actin dynamics by western blot. The present study also developed an automatic cell counting system using machine learning to count migrated cells by Fiji and Trainable Weka Segmentation.
6-Hydroxythiobinupharidine inhibited migration of LM8 osteosarcoma cells in a dose-dependent manner, and decreased protein expression of Lin11, Isl-1, and Mec-3 domain kinase 1 (LIMK1) and the levels of phosphorylated Cofilin.
6-Hydroxythiobinupharidine suppressed migration of LM8 osteosarcoma cells by decreasing expression of LIMK1. 6-Hydroxythiobinupharidine could be potentially used as an anti-metastatic compound.
Pneumonia is a common cause of illness and death of the elderly in Japan. Its prevalence is escalating globally with the aging of population. To describe the latest trends in pneumonia ...hospitalizations, especially aspiration pneumonia (AP) cases, we assessed the clinical records of pneumonia patients admitted to core acute care hospitals in Miyagi prefecture, Japan. A retrospective multi-institutional joint research was conducted for hospitalized pneumonia patients aged greater than or equal to20 years from January 2019 to December 2019. Clinical data of patients were collected from the medical records of eight acute care hospitals. Out of the 1,800 patients included in this study, 79% of the hospitalized pneumonia patients were aged above 70 years. The most common age group was in the 80s. The ratio of AP to total pneumonia cases increased with age, and 692 out of 1,800 patients had AP. In univariate analysis, these patients had significantly older ages, lower body mass index (BMI), a lower ratio of normal diet intake and homestay before hospitalization, along with more AP recurrences and comorbidities. During hospitalization, AP patients had extended fasting periods, more swallowing assessments and interventions, longer hospitalization, and higher in-hospital mortality rate than non-AP patients. A total of 7% and 2% AP patients underwent video endoscopy and video fluorography respectively. In multivariate analysis, lower BMI, lower C-reactive protein, a lower ratio of homestay before hospitalization, a higher complication rate of cerebrovascular disease, dementia, and neuromuscular disease were noted as a characteristic of AP patients. Swallowing interventions were performed for 51% of the AP patients who had been hospitalized for more than two weeks. In univariate analysis, swallowing intervention improved in-hospital mortality. Lower AP recurrence before hospitalization and a lower ratio of homestay before hospitalization were indicated as characteristics of AP patients of the swallowing intervention group from multivariate analysis. Change in dietary pattern from normal to modified diet was observed more frequently in the swallowing intervention group. AP accounts for 38.4% of all pneumonia cases in acute care hospitals in Northern Japan. The use of swallowing evaluations and interventions, which may reduce the risk of dysphagia and may associate with lowering mortality in AP patients, is still not widespread.
Bortezomib (Btz) is an active agent used to treat multiple myeloma (MM). Not all patients who receive Btz-containing therapy show a favorable response. Interaction of cellular adhesion molecules with ...MM and bone marrow stromal cells is crucial for the survival of MM cells. However, little is known about the role of these molecules in the sensitivity of MM to Btz-containing therapy. Thus, we evaluated the correlation between the level of cellular adhesion molecules in MM cells and the efficacy of Btz plus dexamethasone (Bd) therapy. The expression of the neural cell adhesion molecule gene (NCAM, also known as CD56), ITGA4, CXCR4, and other genes were analyzed in 74 samples of primary MM cells collected from patients before they received Bd therapy. Of the eight genes tested, expression of NCAM was lower among patients who responded poorly to Bd therapy. In vitro expression of NCAM induced by transfection of MM cells enhanced their sensitivity to Btz treatment by causing accumulation of polyubiquitinated proteins. Our results indicate that expression of NCAM is associated with better response to Btz treatment and is a promising candidate biomarker for predicting response to therapies involving Btz.
Adult T‐cell leukemia/lymphoma (ATL) is caused by Human T‐cell lymphotropic/leukemia virus type 1 (HTLV‐1), and a higher HTLV‐1 provirus load in PBMC is a risk factor for ATL development. Here, we ...document a significant inverse correlation between the function of HTLV‐1 Tax‐specific CTL (Tax‐CTL), as assessed by ex vivo cytokine production in response to cognate peptide, and the HTLV‐1 provirus load in PBMC in both HTLV‐1 asymptomatic carriers (AC) (Spearman rank correlation coefficient Rs = −0.494, P = .037, n = 18) and ATL patients (Rs = −0.774, P = .001, n = 15). There was also a significant correlation between the HTLV‐1 provirus load and the percentage of PD‐1‐positive Tax‐CTL in both HTLV‐1 AC (Rs = 0.574, P = .013) and ATL patients (Rs = 0.676, P = .006). Furthermore, the percentage of PD‐1‐positive Tax‐CTL was inversely correlated with their function in HTLV‐1 AC (Rs = −0.542, P = .020), and ATL patients (Rs = −0.639, P = .010). These findings indicate that the function of Tax‐CTL decreased as their programmed cell death protein 1 (PD‐1) levels increased, parallel to the increased HTLV‐1 provirus load in PBMC. We propose that functional Tax‐CTL are crucial for determining the HTLV‐1 provirus load in PBMC, not only in HTLV‐1 AC, but also in ATL, and that PD‐1 expression levels are reliable markers of Tax‐CTL function. Thus, modulating the immunological equilibrium between Tax‐CTL and HTLV‐1‐infected cells to achieve dominance of functional effectors could represent an ideal strategy for controlling HTLV‐1‐associated disease.
The functional integrity of Tax‐CTL is crucial for determining HTLV‐1 provirus load in PBMC not only in HTLV‐1 AC, but also in ATL patients.
A triruthenium cluster, (μ3,η2,η3,η5-acenaphthylene)Ru3(CO)7 (1) catalyzes the reaction of secondary amides with hydrosilanes, yielding a mixture of secondary amines, tertiary amines, and silyl ...enamines. Production of secondary amines with complete selectivity is achieved by the use of higher concentration of the catalyst (3 mol %) and the use of bifunctional hydrosilanes such as 1,1,3,3-tetramethyldisiloxane. Acidic workup of the reaction mixture affords the corresponding ammonium salts, which can be treated with a base, providing a facile method for isolation of secondary amines with high purity. In contrast, tertiary amines are formed with high selectivity by using lower concentration of the catalyst (1 mol %) and polymeric hydrosiloxanes (PMHS) as reducing agent. Reduction with PMHS encapsulates the ruthenium catalyst and organic byproducts to the insoluble silicone resin. The two reaction manifolds are applicable to various secondary amides and are practical in that the procedures provide the desired secondary or tertiary amine as a single product. The product contaminated with only minimal amounts of ruthenium and silicon residues. On the basis of the products and observed side products as well as NMR studies a mechanistic scenario for the reaction is also described.
X-linked nephrogenic diabetes insipidus (NDI) is caused by variations in arginine vasopressin receptor 2 (AVPR2). Some patients show partial resistance to arginine vasopressin (AVP). A 19-month-old ...Japanese boy presented with polydipsia since infancy. His mother had a history of polydipsia during pregnancy, and his maternal granduncle also had polydipsia. Intermediate urine osmolality and markedly high plasma AVP levels were observed in the water deprivation test. Subsequent pitressin administration caused no further elevation in urine osmolality. We diagnosed the patient with partial NDI, initiated therapy with hydrochlorothiazide, and placed him on a low-sodium diet. Although his urine volume decreased by 20–30% after the initiation of therapy, progressive hydronephrosis and growth retardation developed 2 years later. We investigated his genetic background by multiplex targeted sequencing of genes associated with inherited renal diseases, including AVPR2 and aquaporin-2 (AQP2). We identified a hemizygous missense variant in AVPR2 NM_000054:c.371A>G,p.(Tyr124Cys) in the boy and a heterozygous variant in the mother at the same locus. Distinguishing partial NDI from primary polydipsia is difficult because of its mild symptoms. Markedly elevated plasma AVP levels with intermediate urine osmolality may suggest partial NDI, and genetic analysis can be useful for such patients.
Epithelioid hemangioma is a rare benign vascular tumor that consists of capillary-sized vessels lined by epithelioid endothelial cells. Diffuse cavernous hemangioma is a congenital benign vascular ...neoplasm consisting of increased dilated vessels. We report a case of epithelioid hemangioma and diffuse cavernous hemangioma that co-occurred in the rectum. To our knowledge, this is the first report in which two rare vascular lesions coexisted. Because both epithelioid hemangioma and diffuse cavernous hemangioma are often clinically confounded by malignant tumors, differentiating these benign lesions from other possible malignant tumors is significant.
Phosphoglycerate mutase (PGAM) is an enzyme of intermediary metabolism that converts 3-phosphoglycerate to 2-phosphoglycerate in glycolysis. Here, we discovered PGAM5 that is anchored in the ...mitochondrial membrane lacks PGAM activity and instead associates with the MAP kinase kinase kinase ASK1 and acts as a specific protein Ser/Thr phosphatase that activates ASK1 by dephosphorylation of inhibitory sites. Mutation of an active site His-105 in PGAM5 abolished phosphatase activity with ASK1 and phospho-Thr peptides as substrates. The Drosophila and Caenorhabditis elegans orthologs of PGAM5 also exhibit specific Ser/Thr phosphatase activity and activate the corresponding Drosophila and C. elegans ASK1 kinases. PGAM5 is unrelated to the other known Ser/Thr phosphatases of the PPP, MPP, and FCP families, and our results suggest that this member of the PGAM family has crossed over from small molecules to protein substrates and been adapted to serve as a specialized activator of ASK1.
BAY 1143572 is a highly selective inhibitor of cyclin-dependent kinase 9/positive transcription elongation factor b. It has entered phase I clinical studies. Here, we have assessed the utility of BAY ...1143572 for treating natural killer (NK) cell leukemias/lymphomas that have a poor prognosis, namely extranodal NK/T-cell lymphoma, nasal type and aggressive NK-cell leukemia, in a preclinical mouse model in vivo as well as in tissue culture models in vitro. Seven NK cell leukemia/lymphoma lines and primary aggressive NK-cell leukemia cells from two individual patients were treated with BAY 1143572 in vitro. Primary tumor cells from an aggressive NK-cell leukemia patient were used to establish a xenogeneic murine model for testing BAY 1143572 therapy. Cyclin-dependent kinase 9 inhibition by BAY 1143572 resulted in prevention of phosphorylation at the serine 2 site of the C-terminal domain of RNA polymerase II. This resulted in lower c-Myc and Mcl-1 levels in the cell lines, causing growth inhibition and apoptosis. In aggressive NK-cell leukemia primary tumor cells, exposure to BAY 1143572 in vitro resulted in decreased Mcl-1 protein levels resulting from inhibition of RNA polymerase II C-terminal domain phosphorylation at the serine 2 site. Orally administering BAY 1143572 once per day to aggressive NK-cell leukemia-bearing mice resulted in lower tumor cell infiltration into the bone marrow, liver, and spleen, with less export to the periphery relative to control mice. The treated mice also had a survival advantage over the untreated controls. The specific small molecule targeting agent BAY1143572 has potential for treating NK cell leukemia/lymphoma.
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