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Two spayed female cats presented with hepatic encephalopathy due to hyperammonaemia. On abdominal ultrasound, concurrent portal vein thrombosis and splenosystemic shunts were suspected in both cats. Computed tomographic angiography clearly detected thrombi as non‐contrast enhancing intraluminal structures in the main portal vein of both cats. Additionally, splenorenal shunts were revealed in both cats. Follow‐up computed tomographic angiography for portal vein thrombosis was performed in both cats, only one of whom received anticoagulant therapy. In the untreated cat, portal vein thrombosis had progressed with the development of an aberrant tortuous vessel. In the cat treated with low‐molecular‐weight heparin, the thrombus progressively decreased in size and disappeared on follow‐up diagnostic imaging. Computed tomographic angiography might be useful for the diagnosis and follow‐up of portal vein thrombosis in cats. [ABSTRACT FROM AUTHOR]

Single-pole writers and tunneling magnetoresistive (TMR) readers for 140-Gb/[in.sup.2] perpendicular recording were fabricated and their recording performance was tested. Data erasure, which is observed as write instability in a repeated read-write operation, can be suppressed by combining a laminated pole and low throat height. Fe--Co/Ni--Cr laminated film was used to reduce the remanent magnetization of the main pole after patterning. Narrow track writers with a 120-nm-wide trapezoidal pole showed a good write ability of 30 dB or more in overwrite for media with high coercivity of up to 7 kOe. Also, negligibly small skew writing was confirmed. TMR heads with a sensor width of 85 nm and a head resistance of 250 [ohm] showed approximately 30 dB of head signal-to-noise ratio (SNR). A potentially higher SNR with a higher operating voltage was suggested from a measured output versus sensing current curve. Calculations showed that the side reading was suppressed in a side-shielded design. A 10% amplitude width of the microtrack profile of a 100-nm-wide reader was reduced from 198 to 162 nm by applying the side shields. Index Terms--Laminated pole, perpendicular recording, pole erasure, side shield, single-pole writer, skew writing, TMR heads.

This article discusses the use of electrocardiography-gated non-helical CT angiography in the treatment of patent ductus arteriosus in a small breed dog. The study involved a 6-year-old Maltese dog, and the CT angiography was performed using a 320-row area detector CT. The non-helical method was chosen to overcome the limitations of the helical method and to select the best reconstructed image. The study found that electrocardiography-gated non-helical CT angiography was helpful in selecting an appropriate device option for closing the patent ductus arteriosus. [Extracted from the article]

A 13‐month‐old female Toy Poodle was presented for progressive ataxia and intention tremors of head movement. The diagnosis of Sandhoff's disease (GM2 gangliosidosis) was confirmed by deficient β‐N‐acetylhexosaminidase A and B activity in circulating leukocytes and identification of the homozygous mutation (HEXB: c.283delG). White matter in the cerebrum and cerebellum was hyperintense on T2‐weighted and fluid‐attenuated inversion recovery magnetic resonance images. Over the next 2 years, the white matter lesions expanded, and bilateral lesions appeared in the cerebellum and thalamus, associated with clinical deterioration. Magnetic resonance spectroscopy showed progressive decrease in brain N‐acetylaspartate, and glycine‐myo‐inositol and lactate‐alanine were increased in the terminal clinical stage. The concentrations of myelin basic protein and neuron specific enolase in cerebrospinal fluid were persistently increased. Imaging and spectroscopic appearance correlated with histopathological findings of severe myelin loss in cerebral and cerebellar white matter and destruction of the majority of cerebral and cerebellar neurons. [ABSTRACT FROM AUTHOR]

A 9-year-old female neutered Weimaraner presented with a 2-month history of progressive right head tilt, ataxia and left temporal muscle atrophy. In humans, myxoid meningioma is rare and is a form of metaplastic meningioma, characterised by the proliferation of mesenchymal components, but MRI findings, treatment and outcome do not differ from those associated with typical types of meningioma. Impression smears predominantly consisted of individual round cells (histocytes and plasma cells), suggesting a round cell tumour, such as histiocytic sarcoma (Fig 1C), but the final histopathologic diagnosis was myxoid meningioma (Fig 1D). [Extracted from the article]

Differential diagnosis included intervertebral disc lesions, syringomyelia (SM) associated with Chiari-like malformation (CM) and inflammatory diseases. Syringomyelia fluid flow on time-spatial labeling inversion pulse (Time-SLIP) images in a dog Magnetic resonance imaging revealed CM/SM from C1 to L3 vertebral level, and intervertebral disc herniation with loss of hyperintense signal of the nucleus pulposus suggesting dehydration at C3-4 (Fig 1a-c). [Extracted from the article]

"T-SLIP" MRI imaging of cerebrospinal fluid flow through the mesencephalic aqueduct T-SLIP images were acquired only after surgery (because we needed to limit anaesthesia time when the dog initially presented as an emergency) and confirmed CSF flow through the aqueduct (Fig., Video S1, Supporting information). Before shunting, the lateral and third ventricles are enlarged and CSF signal in the cerebral sulci is not visible (a: arrow heads). [Extracted from the article]

In a 3-year study, seasonal and daily soil water fluctuations in a California blue oak woodland were investigated by measuring soil water potential (Ψs) at hourly intervals. Soil water potential remained relatively high well into the annual summer drought, with values above –0.5 MPa until June even in a dry year. As drought progressed, Ψs (at 25, 50, 75, and 100 cm depth) decreased to less than –3 MPa, providing evidence for continued blue oak root activity throughout the summer. We observed diurnal Ψs fluctuations (gradual increase at night and rapid decrease during daytime) characteristic of hydraulic lift, a process by which plant roots redistribute water from wet to dry soil layers. These diurnal fluctuations were observed at all four soil depths and began to appear when Ψs reached approximately –0.3 MPa. When Ψs reached approximately –3 MPa, fluctuations became "offset" from those typical of hydraulic lift. These offset fluctuations (apparent at low water potentials when temperature fluctuations were large) closely followed diurnal fluctuations in soil temperature. We propose that these offset patterns resulted from a combination of hydraulic lift cessation and an over-correction for temperature in the model used to calculate Ψs from raw sensor data. The appearance and disappearance of hydraulic lift fluctuations seemed to depend on Ψs. While soil temperatures and dates at which hydraulic lift appeared (and disappeared) were significantly different between wet and dry years, Ψs values associated with hydraulic lift appearance were not significantly different. Hydraulic lift occurred too late in summer to benefit annual forage grasses. However, water released by blue oak trees at night could slow the rate of soil water depletion and extend blue oaks' growing season. [ABSTRACT FROM AUTHOR]

Arrow indicates the kidney in the pelvic cavity and arrowhead indicates rectal compression by the kidney. The renal artery to the left kidney starts level with the L6 and L7 vertebrae (arrowhead) and the renal vein from the left kidney ends level with L5 and L6 vertebrae (arrow). Several types of ectopic kidney have been reported in cats including simple ipsilateral/bilateral renal ectopia, complex ectopia and fusion of the kidneys. [Extracted from the article]

In this case, a surgical approach through the temporal bone underintraoperative ultrasound guidance allowed gross resection of the intraventricular tumour without postoperative complications. Postsurgical MRI revealed grossly complete resection of the mass lesion (Fig 1F). A metastatic tumour or high grade glioma - including anaplastic astrocytoma or glioblastoma - was suspected from MR spectroscopy, with decreased N-acetyl aspartate/creatine (Cr) and increased choline/Cr and lipids/Cr. [Extracted from the article]

Both MR myelography techniques add valuable information to confirm the intradural-extramedullary origin of the lesion that is difficult to classify on conventional MR images. Movie of maximum intensity projection (MIP) image which is created using FE3D-SSFP data to observe the lesion from a different angle (starting with a dorsal view of the spinal cord). It is clearly observed that the teardrop-shaped lesion is not connected with the central canal cranially (upper side in the video) but there is a connection between the lesion and subarachnoid space caudally (lower side in the video). [Extracted from the article]

This study investigated causes of attenuation of cerebrospinal fluid (CSF) signal on heavily T2-weighted (T2W) images in dogs with thoracolumbar disc extrusion. Medical records and magnetic resonance images were retrospectively reviewed. Dogs were classified into the following grades; grade 1, non-ambulatory paraparesis; grade 2, paraplegia with deep pain perception and grade 3, paraplegia without deep pain perception. The length of intramedullary T2W hyperintensity of the spinal cord, cranial/ caudal expansion of extradural compressive materials (ECM), and the CSF signal attenuation were measured. Ratios to the second lumbar vertebra (L2) were calculated for the length of intramedullary T2W hyperintensity (T2W:L2), cranial/caudal expansion of ECM (ECML:L2), and CSF signal attenuation (CSF:L2). The dogs were classified into focal or extended T2W hyperintensity groups according to the length [focal, shorter than length of L2; extended, longer than L2]. The area of EMC and the spinal canal were measured on transverse images at the lesion deriving occupancy ratio. The correlation between CSF:L2 and other data were analysed, and CSF:L2 was compared between the grades. In dogs with intramedullary T2W hyperintensity, the locations of CSF attenuation and the hyperintensity were compared if those locations were matched. Fifty-five dogs were included, 36 of which showed intramedullary T2W hyperintensity. Twenty-two of 36 dogs were considered as match of the location of the CSF attenuation and hyperintensity. CSF:L2 was significantly correlated with T2W:L2 in dogs with extended T2W hyperintensity (p = 0.0002), while CSF:L2 was significantly correlated with ECML:L2 in dogs with focal or no T2W hyperintensity (p = 0.0103 and p = 0.0364, respectively). CSF:L2 in grade 3 was significantly greater than those in patients who were grade 1 or 2 (both p < 0.001). In conclusion, higher CSF:L2, which was frequently seen in grade 3, would be most consistent with a higher T2W:L2 which might indicate spinal cord swelling. [ABSTRACT FROM AUTHOR]

Presents an abstract of a study that investigated the sensitivity distribution profiles of magnetoresistive heads using a microtrack technique and computer simulation.

Cerebrospinal fluid (CSF) circulation diseases, such as hydrocephalus and syringomyelia, are common in small-breed dogs. In human patients with CSF circulation diseases, time-spatial labeling inversion pulse (time-SLIP) sequence performed to evaluate CSF flow before and after treatment allows visualization of the restoration of CSF movement. However, studies evaluating CSF flow using the time-SLIP method in small-breed dogs are limited. Therefore, the present study aimed to evaluate intracranial CSF flow on time-SLIP images in small-breed dogs with idiopathic epilepsy, as an alternative model to healthy dogs. Time-SLIP images were obtained at two sites: 1) the mesencephalic aqueduct (MA) area (third ventricle, MA, and brain-base subarachnoid space [SAS]) and 2) the craniocervical junction area (fourth ventricle, brainstem, and cervical spinal cord SAS) to allow subsequent evaluation of the rostral and caudal CSF flow using subjective and objective methods. In total, six dogs were included. Caudal flow at the MA and brain-base SAS and rostral flow in the brainstem SAS were subjectively and objectively observed in all and 5/6 dogs, respectively. Objective evaluation revealed that a significantly smaller movement of the CSF, assessed as the absence of CSF flow by subjective evaluation, could be detected in some areas. In small-breed dogs, the MA, brain-base, and brainstem SAS would be appropriate areas for evaluating CSF movement, either in the rostral or caudal flows on time-SLIP images. In areas where CSF movement cannot detected by subjective methods, an objective evaluation should be conducted.

Objectives: The role of glycogen synthase kinase (GSK)-3β in adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type 1 (HTLV-1) is paradoxical and enigmatic. Here, we investigated the role of GSK-3β and its potential as a therapeutic target for ATL., Methods: Cell proliferation/survival, cell cycle, apoptosis, and reactive oxygen species (ROS) generation were examined using the WST-8 assay, flow cytometry, and Hoechst 33342 staining, respectively. Expression of GSK-3β and cell cycle/death-related proteins, and survival signals was analyzed using RT-PCR, immunofluorescence staining, and immunoblotting., Results: HTLV-1-infected T-cell lines showed nuclear accumulation of GSK-3β. GSK-3β knockdown and its inhibition with 9-ING-41 and LY2090314 suppressed cell proliferation/survival. 9-ING-41 induced G2/M arrest by enhancing the expression of γH2AX, p53, p21, and p27, and suppressing the expression of CDK1, cyclin A/B, and c-Myc. It induced caspase-mediated apoptosis by decreasing the expression of Bcl-xL, Mcl-1, XIAP, c-IAP1/2, and survivin, and increasing the expression of Bak and Bax. 9-ING-41 also induced ferroptosis and necroptosis, promoted JNK phosphorylation, and suppressed IKKγ and JunB expression. It inhibited the phosphorylation of IκBα, Akt, and STAT3/5, induced ROS production, and reduced glycolysis-derived lactate levels., Conclusion: GSK-3β functions as an oncogene in ATL and could be a potential therapeutic target., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Williams receives consulting fees and equity from Ophelia Health Inc, a treatment provider for opioid use disorder.

β-(1,3/1,4)-glucan is a major component of cereal grains, such as oats and barley. In this study, we investigated the effects of cooked waxy barley, which contains β-(1,3/1,4)-glucan, on upper respiratory tract physical symptoms and mood status by performing a randomized, parallel-group, comparative trial. The primary outcome was assessed using the Wisconsin Upper Respiratory Symptom Survey-21 and Profile of Mood States second edition. Twenty-seven healthy Japanese adult participants were supplemented with 100 g of cooked waxy barley (containing 1.8 g of β-glucan) or 100 g of cooked white rice daily for 8 weeks. Participants receiving cooked waxy barley reported a reduction in cumulative days of sneezing ( p < 0.05) and feeling tired ( p < 0.0001) compared with the control group. After the intervention period, there were significantly less severe nasal symptoms, such as runny nose, plugged nose, and sneezing ( p < 0.05), and a significantly greater reduction of the Tension-Anguish score ( p < 0.05) in the barley group than in the control group. This study suggests that supplementation of cooked waxy barley containing β-(1,3/1,4)-glucan prevents or alleviates nasal upper respiratory tract symptoms and improves mood status. The findings of this study should be confirmed by double-blind trials with a larger number of participants.

Introduction: Biological invasions may promote the onset of systemic inflammatory response syndrome in patients eligible for continuous renal replacement therapy (CRRT), leading to poor prognosis. Hence, we aimed to examine the inflammatory reactions in circulation using vitamin E-coated polysulfone hollow fiber membrane (ViLIFE)., Methods: Lipopolysaccharides were intravenously administered to pigs (2 μg/kg/30 min) to establish an acute inflammation model. Extracorporeal circulation was performed for 6 h in continuous venovenous hemodiafiltration mode using a hemofilter for CRRT filled with a polysulfone hollow fiber membrane or ViLIFE, and the differences in inflammatory reactions were evaluated., Results: The ViLIFE group exhibited low platelet and cytokine levels (p < 0.05 vs. sham-CRRT group). Additionally, the ViLIFE group had lower lactate and high mobility group box 1 levels than the other groups., Conclusion: ViLIFE represents a promising CRRT modality that can inhibit the inflammatory response in circulation and inhibit further biological invasions., (© 2024 The Author(s). Therapeutic Apheresis and Dialysis published by John Wiley & Sons Australia, Ltd on behalf of International Society for Apheresis and Japanese Society for Apheresis.)

Objectives: We aimed to determine the role of dihydroorotate dehydrogenase (DHODH) in pathogenesis of adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type 1 (HTLV-1) and the effects of its inhibition on the de novo pyrimidine biosynthesis pathway., Methods: Cell proliferation, viability, cycle, and apoptosis were analyzed using WST-8 assays, flow cytometry, and Hoechst 33342 staining. To elucidate the molecular mechanisms involved in the anti-ATL effects of DHODH knockdown and inhibition, RT-PCR and immunoblotting were conducted., Results: HTLV-1-infected T-cell lines aberrantly expressed DHODH. Viral infection and the oncoprotein, Tax, enhanced DHODH expression, while knockdown of DHODH decreased HTLV-1-infected T-cell growth. In addition, BAY2402234, a DHODH inhibitor, exerted an anti-proliferative effect, which was reversed by uridine supplementation. BAY2402234 induced DNA damage and S phase arrest by downregulating c-Myc, CDK2, and cyclin A and upregulating p53 and cyclin E. It also induced caspase-mediated apoptosis by the upregulation of pro-apoptotic and downregulation of anti-apoptotic proteins. Furthermore, BAY2402234 induced caspase-independent ferroptosis and necroptosis. It decreased phosphorylation of IKK, IκBα, PTEN, Akt, and its downstream targets, suggesting that inhibition of NF-κB and Akt signaling is involved in its anti-ATL action., Conclusion: These findings highlight DHODH as a potential therapeutic target for treating ATL., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Adult T-cell leukemia (ATL), caused by HTLV-1, is the most lethal hematological malignancy. NEDD8-activating enzyme (NAE) is a component of the NEDD8 conjunction pathway that regulates cullin-RING ubiquitin ligase (CRL) activity. HTLV-1-infected T cells expressed higher levels of NAE catalytic subunit UBA3 than normal peripheral blood mononuclear cells. NAE1 knockdown inhibited proliferation of HTLV-1-infected T cells. The NAE1 inhibitor MLN4924 suppressed neddylation of cullin and inhibited the CRL-mediated turnover of tumor suppressor proteins. MLN4924 inhibited proliferation of HTLV-1-infected T cells by inducing DNA damage, leading to S phase arrest and caspase-dependent apoptosis. S phase arrest was associated with CDK2 and cyclin A downregulation. MLN4924-induced apoptosis was mediated by the upregulation of pro-apoptotic and downregulation of anti-apoptotic proteins. Furthermore, MLN4924 inhibited NF-κB, AP-1, and Akt signaling pathways and activated JNK. Therefore, neddylation inhibition is an attractive strategy for ATL therapy. Our findings support the use of MLN4924 in ATL clinical trials.

Background: Current treatment of major depressive disorder is facing challenges, including a low remission rate, late onset of efficacy, and worsening severity due to comorbid symptoms such as psychosis and cognitive dysfunction. Serotonin (5-HT) neurotransmission is involved in a wide variety of psychiatric diseases and its potential as a drug target continues to attract attention., Objectives: The present study elucidates the effects of a novel 5-HT modulator, DSP-6745, on depression and its comorbid symptoms., Results: In vitro radioligand binding and functional assays showed that DSP-6745 is a potent inhibitor of 5-HT transporter and 5-HT 2A , 5-HT 2C , and 5-HT 7 receptors. In vivo, DSP-6745 (6.4 and 19.1 mg/kg as free base, p.o.) increased the release of not only 5-HT, norepinephrine, and dopamine, but also glutamate in the medial prefrontal cortex. The results of in vivo mouse phenotypic screening by SmartCube® suggested that DSP-6745 has a behavioral signature combined with antidepressant-, anxiolytic-, and antipsychotic-like signals. A single oral dose of DSP-6745 (6.4 and 19.1 mg/kg) showed rapid antidepressant-like efficacy in the rat forced swim test, even at 24 h post-dosing, and anxiolytic activity in the rat social interaction test. Moreover, DSP-6745 (12.7 mg/kg, p.o.) led to an improvement in the apomorphine-induced prepulse inhibition deficit in rats. In the marmoset object retrieval with detour task, which is used to assess cognitive functions such as attention and behavioral inhibition, DSP-6745 (7.8 mg/kg, p.o.) enhanced cognition., Conclusions: These data suggest that DSP-6745 is a multimodal 5-HT receptor antagonist and a 5-HT transporter inhibitor and has the potential to be a rapid acting antidepressant with efficacies in mitigating the comorbid symptoms of depression., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Sugarcane ( Saccharum spp. hybrids) and its processed products have supported local industries such as those in the Nansei Islands, Japan. To improve the sugarcane quality and productivity, breeders select better clones by evaluating agronomic characteristics, such as commercially recoverable sugar and cane yield. However, other constituents in sugarcane remain largely unutilized in sugarcane breeding programs. This study aims to establish a data-driven approach to analyze agronomic characteristics from breeding programs. This approach also determines a correlation between agronomic characteristics and free amino acid composition to make breeding programs more efficient. Sugarcane was sampled in clones in the later stage of breeding selection and cultivars from experimental fields on Tanegashima Island. Principal component analysis and hierarchical cluster analysis using agronomic characteristics revealed the diversity and variability of each sample, and the data-driven approach classified cultivars and clones into three groups based on yield type. A comparison of free amino acid constituents between these groups revealed significant differences in amino acids such as asparagine and glutamine. This approach dealing with a large volume of data on agronomic characteristics will be useful for assessing the characteristics of potential clones under selection and accelerating breeding programs.

Objectives: The cytokine oncostatin M (OSM) elicits pathogenic effects involving disruption of the epithelial barrier function as a part of immunological response networks. It is unclear how these integrated cytokine signals influence inflammation and other physiological processes in the pathology of chronic rhinosinusitis (CRS). We investigated the expression and distribution of OSM and OSM receptor (OSMR) in CRS patients' sinonasal specimens, and we compared the results with a panel of inflammatory cytokine levels and clinical features., Patients and Methods: We classified CRS patients as eosinophilic (ECRS, n = 36) or non-eosinophilic (non-ECRS, n = 35) based on the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis phenotypic criteria and compared their cases with those of 20 control subjects. We also examined OSM's stimulatory effects on cytokine receptor expression levels using the human bronchial epithelium cell line BEAS-2B., Results: RT-PCR showed that the OSM mRNA levels were significantly increased in the CRS patients' ethmoid sinus mucosa. The OSM mRNA levels were positively correlated with those of TNF-α, IL-1β, IL-13, and OSMR-β. In BEAS-2B cells, OSM treatment induced significant increases in the OSMRβ, IL-1R1, and IL-13Ra mRNA levels., Conclusions: OSM is involved in the pathogenesis of CRS in both type 1 and type 2 inflammation, suggesting the OSM signaling pathway as a potential therapeutic target for modulating epithelial stromal interactions.

Course-based Undergraduate Research Experiences (CUREs) are attractive solutions for scaling undergraduate research experiences at primarily undergraduate teaching institutions, where resources for faculty research activities can be limited. The Sustainable Interdisciplinary Research to Inspire Undergraduate Success (SIRIUS) project is a unique program that integrates CUREs, coordinated around a local real-world problem, throughout a biology department's curricula. The CUREs are scaffolded to provide all biology majors with multiple opportunities to engage in scientific investigations as they advance through introductory, intermediate, and advanced courses. In this mixed methods, cross-sectional study, we explore students' perceptions of the authenticity of their experiences as they progress through the SIRIUS CUREs. Triangulated data collected from two instruments indicated that students in advanced courses recognized more involvement in research activities and perceived greater authenticity in the science they were performing compared with introductory and intermediate students. Intermediate and advanced students perceived more opportunities for independence; however, experiences with failure and the influence these experiences had on the perceptions of authenticity was primarily observed with advanced students. This study contributes to the growing literature on CUREs with a focus on students from a primarily undergraduate institution with multiple minority-serving designations.

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intermittent itchy rash. Type 2 inflammatory cytokines such as interleukin (IL)-4, IL-13, and IL-31 are strongly implicated in AD pathogenesis. Stimulation of IL-31 cognate receptors on C-fiber nerve endings is believed to activate neurons in the dorsal root ganglion (DRG), causing itch. The IL-31 receptor is a heterodimer of OSMRβ and IL31RA subunits, and OSMRβ can also bind oncostatin M (OSM), a pro-inflammatory cytokine released by monocytes/macrophages, dendritic cells, and T lymphocytes. Further, OSM expression is enhanced in the skin lesions of AD and psoriasis vulgaris patients., Objective: The current study aimed to examine the contributions of OSM to AD pathogenesis and symptom expression., Methods: The expression levels of the OSM gene ( OSM ) and various cytokine receptor genes were measured in human patient skin samples, isolated human monocytes, mouse skin samples, and mouse DRG by RT-qPCR. Itching responses to various pruritogens were measured in mice by counting scratching episodes., Results: We confirmed overexpression of OSM in skin lesions of patients with AD and psoriasis vulgaris. Monocytes isolated from the blood of healthy subjects overexpressed OSM upon stimulation with IL-4 or GM-CSF. Systemic administration of OSM suppressed IL31RA expression in the mouse DRG and IL-31-stimulated scratching behavior. In contrast, systemic administration of OSM increased the expression of IL-4- and IL-13-related receptors in the DRG., Conclusion: These results suggest that OSM is an important cytokine in the regulation of skin monocytes, promoting the actions of IL-4 and IL-13 in the DRG and suppressing the action of IL-31. It is speculated that OSM released from monocytes in skin modulates the sensitivity of DRG neurons to type 2 inflammatory cytokines and thereby the severity of AD-associated skin itch., Competing Interests: AT has received honoraria from Eli Lilly, Kaken Seiyaku, Sanofi, Taiho Pharma, Abbie, Pfizer, Kyorin Pharmaceutical, Mitsubishi-Tanabe, Torii Pharmaceutical, and Maruho as a speaker as well as research grants from Eli Lilly, Sanofi, Teijin Pharma, Taiho Pharma, Mitsubishi-Tanabe, Torii Pharmaceutical, and Maruho. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2023 Suehiro, Numata, Saito, Yanagida, Ishikawa, Uchida, Kawaguchi, Yanase, Ishiuji, McGrath and Tanaka.)

In higher education, syllabi have traditionally served as written contracts between instructors and their students, providing first-hand information about the course and expectations. Reading the syllabus may provide students with first impressions or mental images of the instructor, thereby initiating a student-instructor relationship even before any interaction has occurred. Instructors can use syllabi to directly communicate values and practices of equity and inclusion, but students can perceive indirect messages through tone and language that may support or contradict stated values. Here, we share empirically derived recommendations for improving the tone of syllabi with inviting language and stylistic features that promote relationship-building with students., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Chandar et al.)

Inflammation is associated with the pathogenesis of myelodysplastic syndromes (MDS) and emerging evidence suggests that MDS hematopoietic stem and progenitor cells (HSPC) exhibit an altered response to inflammation. Deletion of chromosome 5 (del(5q)) is the most common chromosomal abnormality in MDS. Although this MDS subtype contains several haploinsufficient genes that impact innate immune signaling, the effects of inflammation on del(5q) MDS HSPC remains undefined. Utilizing a model of del(5q)-like MDS, inhibiting the IRAK1/4-TRAF6 axis improved cytopenias, suggesting that activation of innate immune pathways contributes to certain clinical features underlying the pathogenesis of low-risk MDS. However, low-grade inflammation in the del(5q)-like MDS model did not contribute to more severe disease but instead impaired the del(5q)-like HSPC as indicated by their diminished numbers, premature attrition and increased p53 expression. Del(5q)-like HSPC exposed to inflammation became less quiescent, but without affecting cell viability. Unexpectedly, the reduced cellular quiescence of del(5q) HSPC exposed to inflammation was restored by p53 deletion. These findings uncovered that inflammation confers a competitive advantage of functionally defective del(5q) HSPC upon loss of p53. Since TP53 mutations are enriched in del(5q) AML following an MDS diagnosis, increased p53 activation in del(5q) MDS HSPC due to inflammation may create a selective pressure for genetic inactivation of p53 or expansion of a pre-existing TP53-mutant clone.

Dysregulation of innate immune signaling is a hallmark of hematologic malignancies. Recent therapeutic efforts to subvert aberrant innate immune signaling in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have focused on the kinase IRAK4. IRAK4 inhibitors have achieved promising, though moderate, responses in preclinical studies and clinical trials for MDS and AML. The reasons underlying the limited responses to IRAK4 inhibitors remain unknown. In this study, we reveal that inhibiting IRAK4 in leukemic cells elicits functional complementation and compensation by its paralog, IRAK1. Using genetic approaches, we demonstrate that cotargeting IRAK1 and IRAK4 is required to suppress leukemic stem/progenitor cell (LSPC) function and induce differentiation in cell lines and patient-derived cells. Although IRAK1 and IRAK4 are presumed to function primarily downstream of the proximal adapter MyD88, we found that complementary and compensatory IRAK1 and IRAK4 dependencies in MDS/AML occur via noncanonical MyD88-independent pathways. Genomic and proteomic analyses revealed that IRAK1 and IRAK4 preserve the undifferentiated state of MDS/AML LSPCs by coordinating a network of pathways, including ones that converge on the polycomb repressive complex 2 complex and JAK-STAT signaling. To translate these findings, we implemented a structure-based design of a potent and selective dual IRAK1 and IRAK4 inhibitor KME-2780. MDS/AML cell lines and patient-derived samples showed significant suppression of LSPCs in xenograft and in vitro studies when treated with KME-2780 as compared with selective IRAK4 inhibitors. Our results provide a mechanistic basis and rationale for cotargeting IRAK1 and IRAK4 for the treatment of cancers, including MDS/AML., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Acute myeloid leukemia (AML) is an aggressive blood cancer that stems from the rapid expansion of immature leukemic blasts in the bone marrow. Mutations in epigenetic factors represent the largest category of genetic drivers of AML. The chromatin assembly factor CHAF1B is a master epigenetic regulator of transcription associated with self-renewal and the undifferentiated state of AML blasts. Upregulation of CHAF1B, as observed in almost all AML samples, promotes leukemic progression by repressing the transcription of differentiation factors and tumor suppressors. However, the specific factors regulated by CHAF1B and their contributions to leukemogenesis are unstudied. We analyzed RNA sequencing data from mouse MLL-AF9 leukemic cells and bone marrow aspirates, representing a diverse collection of pediatric AML samples and identified the E3 ubiquitin ligase TRIM13 as a target of CHAF1B-mediated transcriptional repression associated with leukemogenesis. We found that CHAF1B binds the promoter of TRIM13, resulting in its transcriptional repression. In turn, TRIM13 suppresses self-renewal of leukemic cells by promoting pernicious entry into the cell cycle through its nuclear localization and catalytic ubiquitination of cell cycle-promoting protein, CCNA1. Overexpression of TRIM13 initially prompted a proliferative burst in AML cells, which was followed by exhaustion, whereas loss of total TRIM13 or deletion of its catalytic domain enhanced leukemogenesis in AML cell lines and patient-derived xenografts. These data suggest that CHAF1B promotes leukemic development, in part, by repressing TRIM13 expression and that this relationship is necessary for leukemic progression., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Patients with adult T-cell leukemia (ATL), which is caused by human T-cell leukemia virus type 1 (HTLV-1), show poor prognosis because of drug resistance. Heat shock protein (HSP) 90 is reportedly essential for ATL cell survival as it regulates important signaling pathways, thereby making HSP90 inhibitors new therapeutic candidates for ATL. However, HSP90 inhibition increases the expression of other HSPs, suggesting that HSPs may contribute to drug resistance. The heat shock factor 1 (HSF1) transcription factor is the primary regulator of the expression of HSPs. Furthermore, targeting HSF1 disrupts the HSP90 chaperone function. Herein, we demonstrated that HSF1 is overexpressed in HTLV-1-infected T cells. HSF1 knockdown inhibited the proliferation of HTLV-1-infected T cells. HSF1 inhibitor KRIBB11 reduced the expression and phosphorylation of HSF1, downregulated HSP70 and HSP27 expression, and suppressed Akt, nuclear factor-κB, and AP-1 signals. KRIBB11 treatment induced DNA damage, upregulated p53 and p21, and reduced the expression of cyclin D2/E, CDK2/4, c-Myc, MDM2, and β-catenin, thereby preventing retinoblastoma protein phosphorylation and inhibiting G1-S cell cycle progression. KRIBB11 also induced caspase-mediated apoptosis concomitant with the suppression of Bcl-xL, Mcl-1, XIAP, c-IAP1/2, and survivin expression. KRIBB11 inhibited HSP70 and HSP90 upregulation through treatment with AUY922, an HSP90 inhibitor, and enhanced the cytotoxic effect of AUY922, suggesting a salvage role of HSF1-dependent HSP induction in response to drug treatment. Finally, treatment of mice with KRIBB11 reduced ATL tumor growth. Therefore, this study provides a strong rationale to target HSF1 and validates the anti-ATL activity of KRIBB11., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Legg-Calvé-Perthes disease (LCPD) is a childhood hip disease characterized by osteonecrosis of the femoral head. Because severe deformity of the femoral head can cause secondary osteoarthritis in adulthood, progressive collapse should be prevented in children with a necrotic epiphysis. The prognosis of patients with LCPD generally worsens as the age at disease onset increases, and the appropriate treatment for late-onset LCPD remains unclear. Based on the limited effect of nonoperative treatment using a nonweightbearing brace, flexion varus osteotomy (FVO) was introduced in 2010 as an initial treatment for late-onset LCPD in place of brace treatment, which we used in our institution before that time., Questions/purposes: We asked, (1) Which treatment, FVO or a nonweightbearing brace, is associated with a lower likelihood of progressive femoral head collapse in children whose diagnosis of LCPD was made at the age of ≥ 8 years and who were followed for a minimum of 3 years after their intervention? (2) What proportion of patients in the brace group had surgery despite the treatment, and what percentage of children in the FVO group had a second operation to remove hardware and/or additional operations?, Methods: The initial treatment was applied in 181 patients with LCPD between 1995 and 2018 in our institution. Patients whose disease onset was at ≥ 8 years old (late-onset LCPD) with complete clinical and radiologic data were considered potentially eligible. In 2010, treatment for these patients changed from brace treatment to FVO for all patients. A total of 35% (42 of 121) of patients who were treated with a nonweightbearing brace between 1995 and 2009 and 40% (24 of 60) of patients who were treated with FVO between 2010 and 2018 were eligible. Among patients treated with a brace, 21% (nine of 42 patients) were excluded because of hospital transfer (three patients), short-term follow-up (three), the period from onset to the first visit was ≥ 7 months (two), and inability to use the brace because of mental incapacity (one patient). In patients treated with FVO, 12% (three of 24 patients) were excluded (two patients with a period from onset to the first visit ≥ 7 months and one with a comorbidity and multiple-epiphyseal dysplasia). Among the remaining patients, 79% (33 of 42 patients) were classified into the brace group and 88% (21 of 24 patients) were classified into the FVO group for analyses. There were no overlapping patients at the timepoint when the treatment strategy for late-onset LCPD changed. In the FVO group, subtrochanteric osteotomy with 35° to 40° of flexion and 15° to 20° of varus was performed using a locking compression plate for pediatric use. Patient demographics, radiographic parameters, and the assessment of femoral head deformity using the Stulberg classification were compared between the two groups. There was a greater proportion of boys than girls in both groups (brace: 88% and FVO: 86%), and there were no differences in the distribution of genders between the groups (p = 0.82). The right side was more frequently treated in the brace group, but there was no difference in laterality between the groups (brace: 58% right and FVO: 62% left; p = 0.16). There was no difference between groups in the median age at disease onset (9.0 years [range 8.0 to 12.5 years] in the brace group and 9.6 years [range 8.0 to 12.4 years] in the FVO group; p = 0.26). There was no difference between the groups in the period of treatment from onset (1.7 ± 1.9 months in the brace group and 1.5 ± 1.5 months in the FVO group; p = 0.73) or the follow-up period (6.7 ± 2.1 years in the brace group and 6.2 ± 2.1 years in the FVO group; p = 0.41). The LCPD stage at the first visit was assessed using the modified Waldenström classification. The intraobserver and interobserver values of the modified Waldenström classification, evaluated using kappa statistics, were excellent (kappa value 0.89 [95% CI 0.75 to 0.97]; p < 0.01) and good (kappa value 0.65 [95% CI 0.43 to 0.87]; p < 0.01). The radiographic degree of collapse at the maximum fragmentation stage was assessed using the lateral pillar classification. The intraobserver and interobserver reliabilities of the lateral pillar classification were excellent (kappa value 0.84 [95% CI 0.73 to 0.94]; p < 0.01) and excellent (kappa value 0.83 [95% CI 0.71 to 0.94]; p < 0.01). The degree of femoral head deformity at the most recent follow-up examination was compared between the groups in terms of the Stulberg classification, in which Classes I and II were classified as good and Classes III through V were classified as poor. The intraobserver and interobserver reliabilities of the Stulberg classification were good (kappa value 0.74 [95% CI 0.55 to 0.92]; p < 0.01) and good (kappa value 0.69 [95% CI 0.50 to 0.89]; p < 0.01). The evaluators were involved in the patients' clinical care as part of the treating team., Results: Good radiographic results (Stulberg Class I or II) were obtained more frequently in the FVO group (76% [16 of 21 patients]) than in the brace group (36% [12 of 33 patients]), with an odds ratio of 5.6 (95% CI 1.7 to 18.5; p < 0.01). In the brace group, a subsequent femoral varus osteotomy was performed in 18% (six of 33) of patients with progressive collapse and hinge abduction, and implant removal surgery was performed approximately 1 year after the first procedure. This traditional varus osteotomy was occasionally performed in patients who were considered for conversion from nonoperative treatment before 2009 because FVO had not yet been introduced. In the FVO group, all patients (n = 21) had a second procedure to remove the implant at a mean of 10.5 ± 1.2 months postoperatively. Additional procedures were performed in 24% (five of 21) of patients, including a second FVO for progressive collapse (one patient), guided growth for a limb length discrepancy (one patient), and flexion valgus osteotomy for coxa vara in patients with a limb length discrepancy (three patients)., Conclusion: Our historical control study found that FVO may increase the possibility of obtaining good radiographic results (Stulberg Class I or II) compared with brace treatment for patients with late-onset LCPD, although surgical interventions after the first and second implant removal procedures may be indicated. Surgeons can consider FVO if they encounter patients with late-onset LCPD, which is a challenging condition. A larger study with long-term follow-up is needed to confirm the efficacy of FVO., Level of Evidence: Level III, therapeutic study., Competing Interests: Each author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2022 by the Association of Bone and Joint Surgeons.)