Fibronectin on target cells attenuates natural cytotoxicity of NK cells via myeloid immune checkpoint ILT3/LILRB4/gp49B.

Natural killer (NK) cells play pivotal roles in innate immunity as well as in anti-tumor responses via natural killing, while their activity is tightly regulated by cell-surface inhibitory receptors. Immunoglobulin-like transcript 3/leukocyte immunoglobulin-like receptor B4 (ILT3/LILRB4, also known as gp49B in mice) is an inhibitory receptor expressed on activated NK cells as well as myeloid-lineage cells. The common physiologic ligand of human LILRB4 and gp49B was identified very recently as fibronectin, particularly the N-terminal 30 kDa domain (FN30). We hypothesized that LILRB4 could bind fibronectin on target cells in trans together with integrins, classical fibronectin receptors, in cis and deliver an inhibitory signal in NK cells, leading to attenuated natural killing. Flow cytometric and confocal microscopic analyses of NK cell-surface gp49B and integrins suggested that these novel and classical fibronectin receptors, respectively, co-engage fibronectin immobilized on a culture plate. Biochemical analyses indicated that tyrosine phosphorylation of spleen tyrosine kinase was augmented in gp49B-deficient NK cells upon binding to the immobilized fibronectin. While surface fibronectin-poor YAC-1 cells were evenly sensitive as to natural killing of both gp49B-positive and -negative NK cells, the killing of fibronectin-rich Lewis lung carcinoma cells, but not the FN30-knockout cells, was augmented among gp49B-deficient NK cells. These results suggest that the natural cytotoxicity of NK cells is negatively regulated through LILRB4/gp49B sensing fibronectin on target cells, which sheds light on the unexpected role of LILRB4 and fibronectin as a potential attenuator of NK cell cytotoxicity in the tumor microenvironment.

Evaluating the effect of management on patients with oral hypofunction: A longitudinal study.

INTRODUCTION: Declining oral function may affect subsequent physical frailty in the older population. The aim of this longitudinal study was to summarise data on patients who underwent functional oral examination and evaluate the impact of management on patients with oral hypofunction (OHF). METHODS: Dental outpatients aged over 65 years at their initial visit to the Niigata University Hospital received detailed assessment of seven oral function items to diagnose oral hypofunction using diagnostic criteria defined by the Japanese Society of Gerodontology. Patients with OHF at the first assessment received management including oral health guidance for low function and dental treatment. They were re-evaluated approximately 6 months later and the two assessments were compared. According to the results of the second assessment, the patients were divided into two groups: OHF improved and OHF re-diagnosed. RESULTS: Of the 273 patients who underwent the first assessment, 86 (31.5%) were diagnosed with OHF and received management. Of those, 42 (48.8%) completed the second assessment. Comparing the first and second assessment, significant improvement was observed in oral hygiene, occlusal force, tongue-lip motor function of /pa/, mastication and swallowing. The change in values from the first assessment demonstrated a significant difference between the OHF improved and re-diagnosed groups only in occlusal force. CONCLUSION: Management for patients with OHF can contribute to the improvement of poor oral function, and an increase in occlusal force was notable in the recovery from OHF.

Efficacy of Combination Therapy with Lenvatinib and Radioactive Iodine in Thyroid Cancer Preclinical Model.

Patients with differentiated thyroid cancer (DTC) usually have good prognosis, while those with advanced disease have poor clinical outcomes. This study aimed to investigate the antitumor effects of combination therapy with lenvatinib and 131I (CTLI) using three different types of DTC cell lines with different profiling of sodium iodide symporter (NIS) status. The radioiodine accumulation study revealed a significantly increased radioiodine uptake in K1-NIS cells after lenvatinib treatment, while there was almost no uptake in K1 and FTC-133 cells. However, lenvatinib administration before radioiodine treatment decreased radioiodine uptake of K1-NIS xenograft tumor in the in vivo imaging study. CTLI synergistically inhibited colony formation and DTC cell migration, especially in K1-NIS cells. Finally, 131I treatment followed by lenvatinib administration significantly inhibited tumor growth of the NIS-expressing thyroid cancer xenograft model. These results provide important clinical implications for the combined therapy that lenvatinib should be administered after 131I treatment to maximize the treatment efficacy. Our synergistic treatment effects by CTLI suggested its effectiveness for RAI-avid thyroid cancer, which retains NIS function. This potential combination therapy suggests a powerful and tolerable new therapeutic strategy for advanced thyroid cancer.

Impact of oral function on regaining oral intake and adjusting diet forms for acute stroke patients.

BACKGROUND: Outcome prediction for dysphagia recovery is essential for rehabilitation treatment planning. Several studies have reported various predictors for resuming oral feeding after post-stroke dysphagia. However, evidence on oral health and function, a crucial part of feeding, has rarely been reported. Therefore, the goal of this study was to identify the oral status-related factors that could predict oral intake resumption in acute stroke patients. METHODS: 80 acute stroke patients with dysphagia were included. Clinical data, including the changes of general condition, oral and swallowing functions, were collected once a week until discharge. Patients were divided into two groups based on the outcome of the food intake level scale at discharge, and data were compared between the groups. RESULTS: 60 patients had regained complete oral intake before discharge. Multiple logistic regression showed that posterior tongue pressure could significantly predict complete oral intake recovery. Tongue pressure and modified water swallowing test score also significantly influenced diet forms. In addition, Spearman correlation analysis showed that improvement of other oral status-related factors, such as oral moisture and dentition status, also indicated the improvement of diet forms and swallowing function during the hospital stay. CONCLUSION: Tongue pressure measurement could be a useful oral status-related indicator for predicting complete oral intake and adjusting diet forms for acute stroke patients during hospitalization. Acute stroke patients should receive proper oral status evaluation and implementation to enhance functional recovery.

Survey of oral hypofunction in older outpatients at a dental hospital.

BACKGROUND: Oral hypofunction is defined as the reversible stage preceding oral dysfunction. However, its assessment and management need further examination and consideration. OBJECTIVE: The present study aimed to examine the current state of oral hypofunction among outpatients at the university hospital. METHODS: New outpatients underwent medical interviews and detailed assessment of oral hypofunction at their initial visit to our dental department. Oral hypofunction was diagnosed if the results of three of the following seven assessment items were below cut-off values: poor oral hygiene, oral dryness, reduced occlusal force, decreased tongue-lip motor function, decreased tongue pressure, decreased masticatory function and deterioration of swallowing function. The relationships between factors used to diagnose oral hypofunction as well as the distributions of assessment values were clarified. RESULTS: Seventy-five of 209 patients (35.9%) were finally diagnosed with oral hypofunction. Diagnosis of oral hypofunction was significantly related to patient age, Eichner index, a chief complaint of dental or periodontal disease or ill-fitting dentures and a history of neurodegenerative disease. The lowest quintile values for poor oral hygiene, oral dryness and decreased masticatory performance were all above current cut-off values. Reduced occlusal force contributed strongly to the diagnosis of oral hypofunction. CONCLUSION: Oral hypofunction in dental outpatients at a university hospital was associated with patient age, medical history and chief complaint at presentation. Diagnosis of oral hypofunction can be closely related to reduced occlusal force. The validity of cut-off values for assessments of oral hypofunction needs further consideration.

Divinylcarbinol Desymmetrization Strategy: A Concise and Reliable Approach to Chiral Hydroxylated Fatty Acid Derivatives.

By the aid of the catalytic desymmetrization of divinylcarbinol as one-pot asymmetric induction and protection of olefin, asymmetric total syntheses of two chiral hydroxylated fatty acid derivatives were successfully achieved. The desired stereoisomers could be concisely prepared in mild conditions in a highly convergent manner. Thus, this novel strategy can help stereochemical elucidations of natural products, which have difficulties in spectroscopic stereochemical analyses due to their local symmetries in the vicinities of the stereogenic secondary hydroxyl units.

Impact of Oral and Swallowing Function on the Feeding Status of Older Adults in Nursing Homes.

BACKGROUND: To date, there have been few guidelines proposed for adjustment of the food consistency, particularly to match the oral function of older adults, which will guide clinicians and caregivers in appropriately modifying food. OBJECTIVE: We investigated how oral, swallowing, and cognitive conditions of older adults who required daily nursing care in a nursing home were associated with different dietary food consistencies. METHODS: Clinical examinations to record dentition status, swallowing, and cognitive functions were performed, and the feeding status, including the food consistencies and need for assistance at lunchtime, was evaluated in 37 older residents in nursing homes. The swallowing function was assessed by performing a modified water-swallowing test, and food swallowing was tested using pudding and rice crackers. The χ2 test was used to determine the relationships among the parameters. RESULTS: No participants were able to take cooked rice, nor regular and soft side dishes. There was no significant relationship between dentition status and feeding status. Of the participants, 95% ate pudding without any problems and 49% ate rice crackers without any signs of swallowing difficulty such as coughing or stopping chewing. There was a significant relationship between the food test score using a rice cracker and the level of food consistencies, and between the same test score and the level of mealtime assistance, whereby the better the score of the food test using a rice cracker, the better was the level of food consistencies including use of a thickening agent and the better was the level of mealtime assistance. CONCLUSION: The results strongly suggest that the food test using a rice cracker was associated with the level of food consistency and mealtime assistance for older adults in nursing homes.

Investigation into the mobility of elderly patients with pneumonia using triaxial accelerometer data.

OBJECTIVE: This study aimed to clarify the levels of physical activity of elderly pneumonia patients. METHOD: This is a prospective observational study among pneumonia patients who were hospitalized in a clinic within a general and respiratory medicine hospital department, and community-dwelling elderly. Activity levels of 29 elderly patients with pneumonia who were aged >75 years (PP group), and 15 community-dwelling healthy elderly (CD group) were measured. Triaxial accelerometers were attached to the patients' left chest regions from 48 h until 7 days after hospitalization. RESULTS: The time spent in the upright position was 320.0 min/day in the PP group and 729.0 min/day in the CD group. The time spent walking was 3.8 min/day in the PP group, and 71.0 min/day in the CD group. In the PP group, the times spent in the upright position and walking did not increase during the period studied, that is, from 48 h until 7 days after hospitalization. CONCLUSION: The time spent in the upright position and walking among elderly patients with pneumonia did not increase, despite gradual improvement of the disease.

Development of 6-arylcoumarins as nonsteroidal progesterone antagonists. Structure-activity relationships and fluorescence properties.

Progesterone is involved in multiple physiological processes, including female reproduction, via binding to the progesterone receptor (PR). We have developed 6-arylcoumarins such as 5 and 6 as non-steroidal PR antagonists with receptor-binding-dependent fluorescence. In this study, we investigated the structure-activity relationships and fluorescence properties of coumarin derivatives bearing a heterocyclic aromatic moiety. Among these derivatives, 7c (IC50: 34nM) and 10b (IC50: 24nM) showed more potent PR-antagonistic activity than lead compounds 5 (IC50: 500nM) and 6 (IC50: 65nM) in alkaline phosphatase (AP) assay. Compound 9b showed solvent-dependent fluorescence intensity, exhibiting strong fluorescence in the presence of PR LBD only in buffer solution. On the other hand, 10b showed a solvent-dependent shift of the fluorescence maximum wavelength in the presence of PR LBD. These results indicate that 6-arylcoumarin will be a useful scaffold for PR antagonists and fluorescent probes targeting PR.

Desorption of intrinsic cesium from smectite: inhibitive effects of clay particle organization on cesium desorption.

Fine clay particles have functioned as transport media for radiocesium in terrestrial environments after nuclear accidents. Because radiocesium is expected to be retained in clay minerals by a cation-exchange reaction, ascertaining trace cesium desorption behavior in response to changing solution conditions is crucially important. This study systematically investigated the desorption behavior of intrinsic Cs (13 nmol/g) in well-characterized Na-montmorillonite in electrolyte solutions (NaCl, KCl, CaCl2, and MgCl2) under widely differing cation concentrations (0.2 mM to 0.2 M). Batch desorption experiments demonstrated that Cs(+) desorption was inhibited significantly in the presence of the environmental relevant concentrations of Ca(2+) and Mg(2+) (>0.5 mM) and high concentrations of K(+). The order of ability for Cs desorption was Na(+) = K(+) > Ca(2+) = Mg(2+) at the highest cation concentration (0.2 M), which is opposite to the theoretical prediction based on the cation-exchange selectivity. Laser diffraction grain-size analyses revealed that the inhibition of Cs(+) desorption coincided with the increase of the clay tactoid size. Results suggest that radiocesium in the dispersed fine clay particles adheres on the solid phase when the organization of swelling clay particles occurs because of changes in solution conditions caused by both natural processes and artificial treatments.

6-arylcoumarins as novel nonsteroidal type progesterone antagonists: an example with receptor-binding-dependent fluorescence.

Various 6-arylcoumarin derivatives were designed and synthesized as candidate nonsteroidal type progesterone antagonists. 6-Bromocoumarin derivatives were prepared from the corresponding 4-substituted 2-acetoxy-5-bromobenzaldehyde by employing the Still-Gennari modification of the Horner-Wadsworth-Emmons olefination reaction and were converted to 6-arylcoumarins by means of Suzuki-Miyaura cross-coupling reactions. The biological activities of these coumarin derivatives were evaluated by means of alkaline phosphatase assay in the T47D human breast carcinoma cell line. Among the synthesized compounds, 36 (IC(50) = 0.12 µM) and 38 (IC(50) = 0.065 µM), bearing a five-membered heterocycle, showed potent PR antagonist activity. Competitive binding assay showed that compounds 8 and 34 have potent PR binding affinity. The fluorescence of compound 8 was dependent on the solvent properties and was increased in the presence of PR ligand binding domain. This property might be applicable to the development of fluorescence probes for studies on PR.