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Ryotaro Ozasa, Masaaki Hotta, Hideaki Yoshimura, Takahisa Nakanishi, Takeshi Tamaki, Shinya Fujita, Naoto Nakamichi, Michihiko Miyaji, Kazuyoshi Ishii, Tomoki Ito, Shosaku NomuraFirst Department of Internal Medicine, Kansai Medical University, Osaka, JapanAbstract: Plasma cell leukemia (PCL) is a rare disease that represents approximately 4% of plasma cell malignant disorders. PCL consists of two variants: primary PCL presents in patients with no previous history of multiple myeloma, while secondary PCL consists of a leukemic transformation in a previously recognized multiple myeloma. Primary PCL is an extremely resistant, rapidly progressive, fatal disease, with a median overall survival of 6.8 months. There is no standard therapeutic strategy, because no treatment option has been prospectively evaluated. We describe a successful case of newly diagnosed primary PCL, treated with a regimen that included bortezomib, followed by auto stem cell transplantation and nonmyeloablative allogeneic stem cell transplantation. Our patient has maintained remission status for over 12 months since undergoing the allogeneic stem cell transplantation. This strategy is promising for PCL, which, though an extremely resistant disease, may become curable.Keywords: plasma cell leukemia, multiple myeloma, bortezomib, stem cell transplantation

Miyoko Arimoto1, Yutaka Komiyama2, Fumiko Okamae1, Akemi Ichibe1, Setsuko Teranishi1, Hirohiko Tokunaga1, Keiko Nakaya3, Michie Fujiwara3, Manabu Yamaoka4, Shuji Onishi4, Rie Miyamoto5, Naoto Nakamichi5, Shosaku Nomura51Blood Transfusion Unit, Kansai Medical University Takii Hospital, 2Department of Clinical Sciences and Laboratory Medicine, Kansai Medical University, 3Clinical Medical Technology Unit, Kansai Medical University Takii Hospital, 4Blood Transfusion Unit, Kansai Medical University Hirakata Hospital, 5First Department of Internal Medicine, Kansai Medical University, Moriguchi, JapanAbstract: Thrombotic thrombocytopenic purpura (TTP) is a multisystemic microvascular disorder that may be caused by an imbalance between unusually large von Willebrand factor multimers and the cleaving protease ADAMTS13. In acquired TTP, especially in secondary TTP with various underlying diseases, the diagnosis is difficult because there are many cases that do not exhibit severe deficiency of ADAMTS13 or raised levels of ADAMST13 inhibitors. It is well known that collagen disease, malignancy, and hematopoietic stem cell transplantation can be underlying conditions that induce TTP. However, TTP induced by acute pancreatitis, as experienced by our patient, has rarely been reported. Our patient completely recovered with treatments using steroids and plasma exchange (PE) only. In cases where patients develop acute pancreatitis with no apparent causes for hemolytic anemia and thrombocytopenia, the possibility of TTP should be considered. Treatments for TTP including PE should be evaluated as soon as a diagnosis is made.Keywords: thrombotic thrombocytopenic purpura, ADAMTS13, acute pancreatitis, plasma exchange

Targeted therapeutics for high-risk cancers remain an unmet medical need. Here we report the results of a large-scale screen of over 11,000 molecules for their ability to inhibit the survival and growth in vitro of human leukemic cells from multiple sources including patient samples, de novo generated human leukemia models, and established human leukemic cell lines. The responses of cells from de novo models were most similar to those of patient samples, both of which showed striking differences from the cell-line responses. Analysis of differences in subtype-specific therapeutic vulnerabilities made possible by the scale of this screen enabled the identification of new specific modulators of apoptosis, while also highlighting the complex polypharmacology of anti-leukemic small molecules such as shikonin. These findings introduce a new platform for uncovering new therapeutic options for high-risk human leukemia, in addition to reinforcing the importance of the test sample choice for effective drug discovery., (© 2024. The Author(s).)

The period of circadian clocks is maintained at close to 24 hours over a broad range of physiological temperatures due to temperature compensation of period length. Here, we show that the quantitative control of the core clock proteins TIMING OF CAB EXPRESSION 1 [TOC1; also known as PSEUDO-RESPONSE REGULATOR 1 (PRR1)] and PRR5 is crucial for temperature compensation in Arabidopsis thaliana . The prr5 toc1 double mutant has a shortened period at higher temperatures, resulting in weak temperature compensation. Low ambient temperature reduces amounts of PRR5 and TOC1. In low-temperature conditions, PRR5 and TOC1 interact with LOV KELCH PROTEIN 2 (LKP2), a component of the E3 ubiquitin ligase Skp, Cullin, F-box (SCF) complex. The lkp2 mutations attenuate low temperature-induced decrease of PRR5 and TOC1, and the mutants display longer period only at lower temperatures. Our findings reveal that the circadian clock maintains its period length despite ambient temperature fluctuations through temperature- and LKP2 -dependent control of PRR5 and TOC1 abundance.

Background: Inflammatory bowel diseases are chronic disabling conditions with a complex and multifactorial etiology, still incompletely understood. OCTN1, an organic cation transporter, could have a role in modulating the inflammatory response, and some genetic polymorphisms of this molecule have been associated with increased risk of inflammatory bowel diseases. Until now, limited information exists on its potential in predicting/modulating patient's response to therapies. The aim of this study was to evaluate the role of OCTN1 in modifying gut microbiota and mucosal immunity in response to infliximab therapy in murine colitis., Methods: A dextran sodium sulphate model of colitis was used to assess the clinical efficacy of infliximab administered intravenously in ocnt1 gene knockout mice and their C57BL/6 controls. Stool, colon, and mesenteric lymph node samples were collected to evaluate differences in gut microbiota composition, histology, and T cell populations, respectively., Results: Octn1 -/- influences the microbiota profile and is associated with a worse dysbiosis in mice with colitis. Infliximab treatment attenuates colitis-associated dysbiosis, with an increase of bacterial richness and evenness in both strains. In comparison with wild type, octn1-/- mice have milder disease and a higher baseline percentage of Treg, Tmemory, Th2 and Th17 cells., Conclusions: Our data support the murine model to study OCTN1 genetic contribution to inflammatory bowel diseases. This could be the first step towards the recognition of this membrane transporter as a biomarker in inflammatory conditions and a predictor of response to therapies., (© 2024 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

This longitudinal study investigated the roles of elementary schoolers' executive function (EF) and theory of mind (ToM) as predictors in their academic achievements in Japanese language skills (e.g., speaking and listening ability, writing ability, reading ability, and linguistic knowledge) from first through fifth grade. We assessed the EF, ToM, and academic achievements of 85 Japanese elementary schoolers, when they were grade 1 ( M = 90.19 months) and grade 3 ( M = 114.34 months). Moreover, academic achievements of same children tested in grade 5 ( M = 137.92 months). A path analysis revealed that EF abilities in Grades 1 and 3 predicted Japanese language achievement via ToM ability, and EF and ToM in Grade 1 had an indirect effect on achievements in Grades 3 and 5. Further, Japanese language skills achievement in Grade 1 predicted EF ability in Grade 3 and EF predicted achievement in Grade 5. These findings indicate the vital role of elementary schoolers' EF on academic achievement in Japan., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

As loneliness is a risk factor for mental and physical health problems in various age groups, this study aimed to explore the impact of the intergenerational Shokuiku (food and nutrition education) program (IGSP) on loneliness in a Japanese community. This single-arm intervention study conducted between 2022 and 2023 included children (n = 21), guardians (n = 16), university students (n = 3), and older adults (n = 6). The IGSP was a one-day program that included participants making and eating their own bread, butter, and sorbet. Loneliness was measured using the Five-item Loneliness Scale for Children (Five-LSC; Japanese) and the three-item UCLA Loneliness Scale (Japanese; for adults) with other direct questions. Social capital, including civic participation, social cohesion, and reciprocity, was assessed using a self-administered questionnaire. The Five-LSC score significantly decreased post-intervention ( p = 0.04). There was a significant increase in adults who reported not feeling lonely ( p = 0.001). However, the UCLA Loneliness Scale scores did not show any significant changes. A positive change in social cohesion, including community contribution ( p = 0.001) and attachment ( p = 0.002), was observed among adults. This study suggests that IGSPs have a positive impact on loneliness in children and a partly positive one in adults. These findings emphasize the potential of intergenerational programs to reduce loneliness in communities.

Background: Sudden sensorineural hearing loss with vertigo (SHLV) and vestibular neuritis (VN) can result in prolonged dizziness., Objectives: This study aimed to compare the video head impulse test (vHIT) of patients with SHLV and VN., Methods: Fifteen patients with SHLV and 21 patients with VN who visited the Vertigo/Dizziness Center of our hospital between December 2016 and February 2023 were included. vHIT was performed at the time of admission, and the VOR gain and catch up saccade (CUS) in the three types of semicircular canals (SCCs) were analyzed., Results: Pathologic vHIT results were observed most frequently in the posterior SCC (73%), followed by lateral (53%) and anterior (13%) SCCs in the SHLV group. In contrast, pathologic vHIT results were observed most frequently in the lateral SCC (100%), followed by the anterior (43%) and posterior SCC (24%) SCCs in the VN group. Pathological vHIT results in the lateral and posterior SCC showed significant differences between the two groups, but for anterior SCC, no significant differences were found., Conclusions and Significance: Comparison of the two vHIT results revealed differences in the SCC dysfunction patterns. This may be due to the different pathophysiological mechanisms of the two vestibular disorders, which may result in prolonged vertigo.