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Most eukaryotes harbor two distinct pre-mRNA splicing machineries: the major spliceosome, which removes >99% of introns, and the minor spliceosome, which removes rare, evolutionarily conserved introns. Although hypothesized to serve important regulatory functions, physiologic roles of the minor spliceosome are not well understood. For example, the minor spliceosome component ZRSR2 is subject to recurrent, leukemia-associated mutations, yet functional connections among minor introns, hematopoiesis and cancers are unclear. Here, we identify that impaired minor intron excision via ZRSR2 loss enhances hematopoietic stem cell self-renewal. CRISPR screens mimicking nonsense-mediated decay of minor intron-containing mRNA species converged on LZTR1, a regulator of RAS-related GTPases. LZTR1 minor intron retention was also discovered in the RASopathy Noonan syndrome, due to intronic mutations disrupting splicing and diverse solid tumors. These data uncover minor intron recognition as a regulator of hematopoiesis, noncoding mutations within minor introns as potential cancer drivers and links among ZRSR2 mutations, LZTR1 regulation and leukemias.

T‐cell acute leukemia and lymphoma have a poor prognosis. Although new therapeutic agents have been developed, their therapeutic effects are suboptimal. α‐Pinene, a monoterpene compound, has an antitumor effect on solid tumors; however, few comprehensive investigations have been conducted on its impact on hematologic malignancies. This report provides a comprehensive analysis of the potential benefits of using α‐pinene as an antitumor agent for the treatment of T‐cell tumors. We found that α‐pinene inhibited the proliferation of hematologic malignancies, especially in T‐cell tumor cell lines EL‐4 and Molt‐4, induced mitochondrial dysfunction and reactive oxygen species accumulation, and inhibited NF‐κB p65 translocation into the nucleus, leading to robust apoptosis in EL‐4 cells. Collectively, these findings suggest that α‐pinene has potential as a therapeutic agent for T‐cell malignancies, and further investigation is warranted. [ABSTRACT FROM AUTHOR]

In vivo skin sensitization tests are required to evaluate the biological safety of medical devices in contact with living organisms to provide safe medical care to patients. Negative and positive reference materials have been developed for biological tests of cytotoxicity, implantation, hemolysis, and in vitro skin irritation. However, skin sensitization tests are lacking. In this study, polyurethane sheets containing 1 wt/wt % 2,4‐dinitrochlorobenzene (DNCB‐PU) were developed and evaluated as a positive reference material for skin sensitization tests. DNCB‐PU sheet extracts prepared with sesame oil elicited positive sensitization responses for in vivo sensitization potential in the guinea pig maximization test and the local lymph node assay. Furthermore, DNCB‐PU sheet extracts prepared with water and acetonitrile, 10% fetal bovine serum‐containing medium, or sesame oil elicited positive sensitization responses as alternatives to animal testing based on the amino acid derivative reactivity assay, human cell line activation test, and epidermal sensitization assay, respectively. These data suggest that the DNCB‐PU sheet is an effective extractable positive reference material for in vivo and in vitro skin sensitization testing in medical devices. The formulation of this reference material will lead to the development of safer medical devices that contribute to patient safety. [ABSTRACT FROM AUTHOR]

Family caregivers' sense of security benefits older adults who receive home care. Advance care planning (ACP) is reported to affect family caregivers' experience positively, but it might differ depending on family caregivers' kin relationships with the older adults. This study aimed to investigate whether ACP for older adults in home care settings is associated with family caregivers' sense of security and whether such an association depends on the family caregivers' status as spouses or adult children. Clarifying this association may offer practical support for implementing ACP while maintaining family caregivers' sense of security. This study was part of a prospective cohort study in Japan. The participants were older adults who used home-visit nursing services, their family caregivers, and the nurses who cared for them, recruited through the professional associations of home care nurses across Japan. Family caregivers answered a sense of security questionnaire, and the nurses were asked whether ACP was conducted. Data were collected three times from nurses and twice from family caregivers over a three-month period from August 2019 to June 2020. Multivariate logistic regression analyses were performed to examine the association between ACP implementation and positive changes in the sense of security scores after three months. Data from 169 cases were analyzed; 28.1% of the family caregivers were men and 55.6% were spouses. ACP was performed in 53.8% of the cases. The multivariate analysis showed an interactive effect between ACP implementation and family caregivers' kin relationships. For spouses, ACP was significantly associated with a positive change in their sense of security. For adult children, such an association was not found. Thus, ACP might have a positive effect on caregiving spouses' sense of security. Adult child caregivers, who often have multiple responsibilities and have difficulties facing their parents' physical decline, may need support in addition to ACP. [ABSTRACT FROM AUTHOR]

In vivo and in vitro irritation testing is important for evaluating the biological safety of medical devices. Here, the performance of positive reference materials for skin irritation testing was evaluated. Four reference standards, referred to as Y‐series materials, were analyzed: a polyvinyl chloride (PVC) sheet spiked with 0 (Y‐1), 1.0 (Y‐2), 1.5 (Y‐3), or 10 (Y‐4) parts of Genapol X‐080 per 100 parts of PVC by weight. Y‐1, Y‐2, and Y‐3 did not induce skin irritation responses in an in vitro reconstructed human epidermis (RhE) tissue model, as measured by tissue viability or interleukin‐1α release, or in an in vivo intracutaneous response test using rabbits. In contrast, Y‐4 extracts prepared with saline or sesame oil at 37°C and 50°C clearly elicited positive irritation responses, including reduced viability (< 50%) and significantly higher interleukin‐1α release compared with the solvent alone group, in the RhE tissue model and an intracutaneous response test, where substantial necrosis was observed by histopathology. The positive skin irritation responses induced in vitro under various extraction conditions, as well as those elicited in vivo, indicate that Y‐4 is an effective extractable positive control material for in vivo and in vitro skin irritation tests of medical devices. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2807–2814, 2018. [ABSTRACT FROM AUTHOR]

ABSTRACTBackground:The aim of the study was to develop a family conflict scale for family caregivers of persons with dementia in long-term care facilities and to explore the relationship between family conflicts and family support.Methods: The scale was developed through forward- and back-translations, interviews with 12 staff members in long-term care facilities, and cognitive interviews with 12 family caregivers who met operational definitions in this study. The test was conducted with 334 family caregivers and a retest was conducted with 318 family caregivers who had indicated willingness to participate further.Results: The internal consistency was relatively high for all subscales (Cronbach's α >0.87); sufficient retest reliability was demonstrated for all subscales (intraclass correlation coefficient >0.69). Confirmatory factor analysis supported a three-factor model. Convergent and discriminant validity for each of the family conflict scale subscales, family APGAR, and the Symptom Check List-90 Items-Revised were acceptable. Family caregivers who received no family assistance for caregiving perceived more conflict in their family than those receiving family assistance.Conclusions: The Japanese version of the family conflict scale for family caregivers of persons with dementia in long-term care facilities was developed. The reliability and validity of the scale were verified. When providing support to family caregivers in long-term care facilities, it is necessary to consider the family from multiple viewpoints, including family conflicts and support conditions from other family members. [ABSTRACT FROM AUTHOR]

Abstract: Di (2‐ethylhexyl) phthalate (DEHP), a typical plasticizer used for polyvinyl chloride (PVC), is eluted from PVC‐made blood containers and protects against red blood cell (RBC) hemolysis. However, concerns have arisen regarding the reproductive and developmental risks of DEHP in humans, and the use of alternative plasticizers for medical devices has been recommended worldwide. In this study, we propose that the use of a novel plasticizer, 4‐cyclohexene‐1,2‐dicarboxylic acid dinonyl ester (DL9TH), could help produce more useful and safe blood containers. PVC sheet containing DL9TH and di (2‐ethylhexyl) 4‐cyclohexene‐1,2‐dicarboxylate (DOTH) provides comparable or superior protective effects to RBCs relative to PVC sheet containing DEHP or di‐isononyl‐cyclohexane‐1,2‐dicarboxylate (DINCH®, an alternative plasticizer that has been used in PVC sheets for blood containers). The total amount of plasticizer eluted from DOTH/DL9TH‐PVC sheets is nearly the same as that eluted from DEHP‐PVC sheets. In addition, DOTH/DL9TH‐PVC has better cold resistance than DEHP‐ and DINCH®‐PVC sheets. In vitro and in vivo tests for biological safety based on International Organization for Standardization guidelines (10993 series) suggest that the DOTH/DL9TH‐PVC sheet can be used safely. Subchronic toxicity testing of DL9TH in male rats in accordance with the principles of Organisation for Economic Co‐operation and Development Test Guideline 408 showed that DL9TH did not induce adverse effects up to the highest dose level tested (717 mg/kg body weight/day). There were no effects on testicular histopathology and sperm counts, and no indications of endocrine effects: testosterone, thyroid‐stimulating hormone, follicle‐stimulating hormone, and 17β‐estradiol were unchanged by the treatment, compared with the control group. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1052–1063, 2018. [ABSTRACT FROM AUTHOR]

This study aimed to optimize the ratio of dioctyl 4-cyclohexene-1,2-dicarboxylate (DOTH) and di-isononyl-cyclohexane-1,2-dicarboxylate (DINCH®) for use as plasticizers in poly(vinyl chloride) (PVC) sheets. We also evaluated the biological safety of DOTH for its potential to be part of a safe PVC-based blood container. The suppression of hemolysis in mannitol-adenine-phosphate / red cell concentrates (MAP/RCC) with DOTH/(DINCH®-PVC) sheets and the elution of plasticizers from the sheets increased with higher DOTH compositions. The properties of the PVC sheet containing DOTH and DINCH® in the ratio of 25:33 parts against PVC 100 parts as a weight were almost identical to the PVC sheet made of di(2-ethylhexyl) phthalate. From a subchronic toxicity test, DOTH did not show any adverse effects on all organs, including the testes, epididymis, liver, and kidneys. The no-observed-adverse-effect level was 300 mg/kg body weight/day in a rat. These results suggest that DOTH/DINCH® (25:33) is a promising candidate for the replacement of di(2-ethylhexyl) phthalate in blood containers. J. VINYL ADDIT. TECHNOL., 22:520-528, 2016. © 2015 Society of Plastics Engineers [ABSTRACT FROM AUTHOR]