Subchronic tolerance trials of graded oral supplementation with ornithine hydrochloride or citrulline in healthy adults.

Ornithine and citrulline are amino acids used in dietary supplements and nutritional products consumed by healthy consumers, but the safe supplementation levels of these compounds are unknown. The objective of this study was to conduct two 4-week clinical trials to evaluate the safety and tolerability of graded dosages of oral ornithine (as hydrochloride) and citrulline. Healthy male adults (n = 60, age 41.4 ± 1.5 years) completed graded dosages of either ornithine hydrochloride (3.2, 6, 9.2, and 12 g/day) or citrulline (6, 12, 18, and 24 g/day) supplement for 4 weeks with 2-week wash-out periods in between. Primary outcomes included vitals, a broad spectrum of circulating biochemical analytes, body weight, sleep quality, and mental self-assessment. In the ornithine hydrochloride supplementation group, minor increase in plasma aspartic acid and glutamic acid concentrations was observed at the highest intake dosages. In the citrulline supplementation group, minor changes in laboratory data for serum lactate dehydrogenase and plasma amino acid concentration of lysine, methionine, threonine, aspartic acid, glutamic acid, glutamine and ornithine, arginine, and citrulline itself were measured. No other changes in measured parameters were observed, and study subjects tolerated 4-week-long oral supplementation of ornithine hydrochloride or citrulline without treatment-related adverse events. A clinical, no-observed-adverse-effect-level (NOAEL) of ornithine hydrochloride and citrulline supplementation in healthy adult males was determined to be 12 g/day and 24 g/day (4 weeks), respectively.

An optimized reference tissue method for quantification of tau protein depositions in diverse neurodegenerative disorders by PET with 18F-PM-PBB3 (18F-APN-1607).

Positron emission tomography (PET) with 18F-PM-PBB3 (18F-APN-1607, 18F-Florzolotau) enables high-contrast detection of tau depositions in various neurodegenerative dementias, including Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). A simplified method for quantifying radioligand binding in target regions is to employ the cerebellum as a reference (CB-ref) on the assumption that the cerebellum has minimal tau pathologies. This procedure is typically valid in AD, while FTLD disorders exemplified by progressive supranuclear palsy (PSP) are characterized by occasional tau accumulations in the cerebellum, hampering the application of CB-ref. The present study aimed to establish an optimal method for defining reference tissues on 18F-PM-PBB3-PET images of AD and non-AD tauopathy brains. We developed a new algorithm to extract reference voxels with a low likelihood of containing tau deposits from gray matter (GM-ref) or white matter (WM-ref) by a bimodal fit to an individual, voxel-wise histogram of the radioligand retentions and applied it to 18F-PM-PBB3-PET data obtained from age-matched 40 healthy controls (HCs) and 23 CE, 40 PSP, and five other tau-positive FTLD patients. PET images acquired at 90-110 min after injection were averaged and co-registered to corresponding magnetic resonance imaging space. Subsequently, we generated standardized uptake value ratio (SUVR) images estimated by CB-ref, GM-ref and WM-ref, respectively, and then compared the diagnostic performances. GM-ref and WM-ref covered a broad area in HCs and were free of voxels located in regions known to bear high tau burdens in AD and PSP patients. However, radioligand retentions in WM-ref exhibited age-related declines. GM-ref was unaffected by aging and provided SUVR images with higher contrast than CB-ref in FTLD patients with suspected and confirmed corticobasal degeneration. The methodology for determining reference tissues as optimized here improves the accuracy of 18F-PM-PBB3-PET measurements of tau burdens in a wide range of neurodegenerative illnesses.

A Machine Learning-Based Approach to Discrimination of Tauopathies Using [18 F]PM-PBB3 PET Images.

BACKGROUND: We recently developed a positron emission tomography (PET) probe, [18 F]PM-PBB3, to detect tau lesions in diverse tauopathies, including mixed three-repeat and four-repeat (3R + 4R) tau fibrils in Alzheimer's disease (AD) and 4R tau aggregates in progressive supranuclear palsy (PSP). For wider availability of this technology for clinical settings, bias-free quantitative evaluation of tau images without a priori disease information is needed. OBJECTIVE: We aimed to establish tau PET pathology indices to characterize PSP and AD using a machine learning approach and test their validity and tracer capabilities. METHODS: Data were obtained from 50 healthy control subjects, 46 patients with PSP Richardson syndrome, and 37 patients on the AD continuum. Tau PET data from 114 regions of interest were subjected to Elastic Net cross-validation linear classification analysis with a one-versus-the-rest multiclass strategy to obtain a linear function that discriminates diseases by maximizing the area under the receiver operating characteristic curve. We defined PSP- and AD-tau scores for each participant as values of the functions optimized for differentiating PSP (4R) and AD (3R + 4R), respectively, from others. RESULTS: The discriminatory ability of PSP- and AD-tau scores assessed as the area under the receiver operating characteristic curve was 0.98 and 1.00, respectively. PSP-tau scores correlated with the PSP rating scale in patients with PSP, and AD-tau scores correlated with Mini-Mental State Examination scores in healthy control-AD continuum patients. The globus pallidus and amygdala were highlighted as regions with high weight coefficients for determining PSP- and AD-tau scores, respectively. CONCLUSIONS: These findings highlight our technology's unbiased capability to identify topologies of 3R + 4R versus 4R tau deposits. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Tolerable amounts of amino acids for human supplementation: summary and lessons from published peer-reviewed studies.

Amino acid supplementation may be indicated to correct for insufficient amino acid intake in healthy individuals, and in specific physiological or pathophysiological situations. However, there is a concern to not supplement beyond the tolerable upper intake level (UL) by determining parameters of no-observed-adverse-effect level (NOAEL) or lowest-observed-adverse-effect level (LOAEL) for each amino acid. Since the NOAEL and LOAEL values are at least one order of magnitude different when comparing the values obtained in rats and humans, the aim of this review is to evaluate to what extent the amino acid UL measured in the rat model, when referenced to the dietary usual consumption (UC) and dietary requirement (RQ) for indispensable amino acids, may be used as an approximation of the UL in humans. This review then compares the ratios of the NOAEL or LOAEL over UC and RQ in the rat model with the same ratios calculated in humans for the nine amino acids (arginine, serine, glycine, histidine, leucine, lysine, methionine, phenylalanine, and tryptophan) for which this comparison can be done. From the calculations made, it appears that for these 9 amino acids, the calculated ratios for rats and humans, although rather different for several amino acids, remains for all of them in the same order of magnitude. For tryptophan, tyrosine, and valine, the ratios calculated in rats are markedly different according to the sex of animals, raising the view that it may be also the case in humans.

In vitro functional analysis of four variants of human asparagine synthetase.

The loss-of-function variants of the human asparagine synthetase (ASNS) gene cause asparagine synthetase deficiency (ASNSD). Diagnosis of ASNSD requires genetic tests because a specific biochemical diagnostic for ASNSD is not available. There are a few reports describing the functional evaluation of ASNS variants. Therefore, in vitro methods are needed to evaluate the detected variants in patients. In this report, five types of human ASNS proteins (wild-type and our reported four variants: p.Leu145Ser, p.Leu247Trp, p.Val489Asp, and p.Trp541Cysfs*5) were expressed in silkworm using a baculoviral expression system. An enzymatic activity assay of ASNS was performed, and the concentration of asparagine by ninhydrin and High Performance Liquid Chromatography methods using the purified recombinant proteins was measured. We established ASNS deficient HEK293 cells using the CRISPR/Cas9 method and evaluated the growth of cells without asparagine after transduction of ASNS variants with a lentiviral expression system. The four ASNS variants displayed significantly low enzymatic activity. The ASNS deficient HEK293 cells transduced with wild-type ASNS grew without asparagine, whereas cells transduced with the variants did not grow or showed significantly slower growth than cells transduced with wild-type ASNS. Herein, we established a method for evaluating the enzymatic activity of the recombinant human ASNS variants. The results of the cell-based assay corroborated the results of the enzymatic activity. These methods should enable the evaluation of the pathogenicity of ASNS variants.

Deficiency of 3-hydroxybutyrate dehydrogenase (BDH1) in mice causes low ketone body levels and fatty liver during fasting.

d-3-Hydroxy-n-butyrate dehydrogenase (BDH1; EC 1.1.1.30), encoded by BDH1, catalyzes the reversible reduction of acetoacetate (AcAc) to 3-hydroxybutyrate (3HB). BDH1 is the last enzyme of hepatic ketogenesis and the first enzyme of ketolysis. The hereditary deficiency of BDH1 has not yet been described in humans. To define the features of BDH1 deficiency in a mammalian model, we generated Bdh1-deficient mice (Bdh1 KO mice). Under normal housing conditions, with unrestricted access to food, Bdh1 KO mice showed normal growth, appearance, behavior, and fertility. In contrast, fasting produced marked differences from controls. Although Bdh1 KO mice survive fasting for at least 48 hours, blood 3HB levels remained very low in Bdh1 KO mice, and despite AcAc levels moderately higher than in controls, total ketone body levels in Bdh1 KO mice were significantly lower than in wild-type (WT) mice after 16, 24, and 48 hours fasting. Hepatic fat content at 24 hours of fasting was greater in Bdh1 KO than in WT mice. Systemic BDH1 deficiency was well tolerated under normal fed conditions but manifested during fasting with a marked increase in AcAc/3HB ratio and hepatic steatosis, indicating the importance of ketogenesis for lipid energy balance in the liver.

Detection and recognition thresholds for five basic tastes in patients with mild cognitive impairment and Alzheimer's disease dementia.

BACKGROUND: Patients with Alzheimer's disease dementia (ADD) are thought to exhibit taste disorders; however, this has not been extensively studied. We investigated gustatory functions and factors affecting taste in patients with ADD or mild cognitive impairment (MCI) and in non-demented controls (NDCs) and evaluated associations between cognitive impairment and gustatory functions. METHODS: We recruited 29 patients with ADD, 43 with MCI, and 14 with NDCs. We obtained medical and medication history, measured salivary secretion volumes, and performed cognitive function tests, blood tests, whole-mouth gustatory tests, and dietary and gustatory questionnaires. RESULTS: Patients with ADD showed significantly higher recognition threshold values than NDCs (p < 0.05). Many individuals did not recognize umami at the maximum concentration, and this happened more frequently in patients with ADD or MCI than in NDCs. Evaluation items other than cognitive function tests did not show significant differences among the groups, but many individuals had decreased salivation, low serum zinc levels, and were on multiple medications. We found a significant correlation between recognition threshold and age (r = 0.229, p < 0.05) and cognitive function test score (r = 0.268, p < 0.05). CONCLUSIONS: Patients with ADD showed impairment of gustatory function. Gustatory impairment in patients with MCI could not be confirmed. However, many individuals with MCI did not recognize umami, either. Our results suggest that taste disorders in elderly people with cognitive decline occur independently of factors affecting taste such as salivation, zinc levels, or prescription drugs. TRIAL REGISTRATION: The study was registered in the UMIN Clinical Trials Registry on February 10, 2017, with reference number UMIN000026087.

Recent advances in understanding beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase, T2) deficiency.

Beta-ketothiolase (mitochondrial acetoacetyl-CoA thiolase, T2) deficiency (OMIM #203750, *607809) is an inborn error of metabolism that affects isoleucine catabolism and ketone body metabolism. This disorder is clinically characterized by intermittent ketoacidotic crises under ketogenic stresses. In addition to a previous 26-case series, four series of T2-deficient patients were recently reported from different regions. In these series, most T2-deficient patients developed their first ketoacidotic crises between the ages of 6 months and 3 years. Most patients experienced less than three metabolic crises. Newborn screening (NBS) for T2 deficiency is performed in some countries but some T2-deficient patients have been missed by NBS. Therefore, T2 deficiency should be considered in patients with severe metabolic acidosis, even in regions where NBS for T2 deficiency is performed. Neurological manifestations, especially extrapyramidal manifestations, can occur as sequelae to severe metabolic acidosis; however, this can also occur in patients without any apparent metabolic crisis or before the onset of metabolic crisis.

Suppression of SESN1 reduces cisplatin and hyperthermia resistance through increasing reactive oxygen species (ROS) in human maxillary cancer cells.

INTRODUCTION: Cisplatin is used as a standard chemotherapeutic agent for head and neck cancer treatment. However, some head and neck cancers have cisplatin resistance, leading to difficulty in treatment and poor prognosis. Overcoming cisplatin resistance remains an important strategy to improve prognoses for head and neck cancer patients. OBJECTIVE: Elucidation of the mechanisms underlying cisplatin resistance can suggest novel targets to enhance the anticancer effects of cisplatin for treating head and neck cancers. MATERIAL AND METHODS: We used a cisplatin-resistant human maxillary cancer cell line, IMC-3CR to analyse the cisplatin resistance mechanisms. Cisplatin-induced genes were analysed in IMC-3CR cells using PCR array. Among the genes with expression increased by cisplatin, we specifically examined SESN1. SESN family reportedly regenerates peroxiredoxin and suppresses oxidative DNA injury by reactive oxygen species (ROS), which can be induced by chemotherapeutic agents such as cisplatin, radiation, and hyperthermia. The function of SESN1 in cisplatin resistance and ROS generation were analysed using specific RNAi. RESULTS: Results show that SESN1 was induced by cisplatin treatment in IMC-3CR cells. Suppression of SESN1 by RNAi induced apoptosis and reduced cell viability through enhancement of ROS after cisplatin treatment. Moreover, suppression of SESN1 enhanced the cell-killing effects of hyperthermia with increased ROS, but did not affect the cell-killing effects of radiation. CONCLUSIONS: This study demonstrated the participation of SESN1 in cisplatin and hyperthermia resistance of human head and neck cancers. SESN1 is a novel molecular target to overcome cisplatin resistance and hyperthermia resistance and improve head and neck cancer treatment.

Thirteen week toxicity study of dietary l-tryptophan in rats with a recovery period of 5 weeks.

Although l-tryptophan is nutritionally important and widely used in medical applications, toxicity data for its oral administration are limited. The purpose of this study was to evaluate the potential toxicity of an experimental diet containing added l-tryptophan at doses of 0 (basal diet), 1.25%, 2.5% and 5.0% when administered to Sprague-Dawley rats for 13 weeks. There were no toxicological changes in clinical signs, ophthalmology, urinalysis, hematology, necropsy, organ weight and histopathology between control rats and those fed additional l-tryptophan. Body weight gain and food consumption significantly decreased throughout the administration period in males in the 2.5% group and in both sexes in the 5.0% group. At the end of the dosing period, decreases in water intake in males in the 5.0% group and in serum glucose in females in the 5.0% group were observed. The changes described above were considered toxicologically significant; however, they were not observed after a 5 week recovery period, suggesting reversibility. Consequently, the no-observed-adverse-effect level of l-tryptophan in the present study was 1.25% for males and 2.5% for females (mean intake of l-tryptophan: 779 mg kg-1 body weight day-1 [males] and 1765 mg kg-1 body weight day-1 [females]). As the basal diet used in this study contained 0.27% of proteinaceous l-tryptophan, the no-observed-adverse-effect level of overall l-tryptophan was 1.52% for males and 2.77% for females (mean intake of overall l-tryptophan: 948 mg kg-1 body weight day-1 (males) and 1956 mg kg-1 body weight day-1 (females)). We conclude that l-tryptophan has a low toxicity profile in terms of human use.

Osborne-Mendel rats simultaneously develop cardiac and renal dysfunction, left atrial thrombosis, peripheral artery occlusion, and ascending aortic dissection.

Although chronic kidney disease (CKD) is strongly associated with onsets of cardiovascular disease (CVD), the pathogenic mechanism between these diseases has not been fully understood. To develop and validate new therapeutic strategies for this complication, appropriate experimental models that reflect the complexity of the underlying pathophysiology are needed. The Osborne-Mendel (OM) rat was identified as an atherosclerosis-prone and a premature-death rat strain among 16 inbred rat strains when fed high-cholesterol containing diet. When fed high-cholesterol diet, OM rats showed simultaneous occurrence of aortic aneurysm, aortic dissection, peripheral artery occlusion, and left atrial thrombosis. OM rats had significantly lower max dP/dt and higher min dP/dt than F344 rats did, indicating impaired left ventricle contractility and relaxation. OM rats developed renal dysfunction, showing increased urinary albumin excretion. OM rats also showed mild hypertension, decreased endothelial function, and enhanced coagulation and platelet aggregation, compared with F344 rats. We now report that OM rat would be a novel spontaneous animal model which simultaneously demonstrates cardiac and renal dysfunction, and CVD events. This model could be a useful model for the pre-clinical testing of pharmacological therapies and could provide new insight into potential targets and pathways for the treatment of CKD and CVD.

Prepubertal onset of slipped capital femoral epiphysis associated with hypothyroidism: a case report and literature review.

BACKGROUND: Slipped capital femoral epiphysis (SCFE) is a common hip disorder characterized by displacement of the capital femoral epiphysis from the metaphysic through the femoral epiphyseal plate. SCFE usually occurs during puberty, with obesity a common risk factor. We experienced a rare case of SCFE associated with hypothyroidism in a prepubescent patient who was not obese. CASE PRESENTATION: The patient was an 8-year-old boy suffering from bilateral SCFE with hypothyroidism. The patient's growth had started to slow at 4 years of age, and at 8 years he was of short stature. During his evaluation for SCFE management, primary hypothyroidism was diagnosed due to the presence of anti-thyroid peroxidase and anti-thyroglobulin antibodies. After the patient was treated for hypothyroidism, which improved his thyroid function, surgery was performed for bilateral SCFE. CONCLUSIONS: Among the 42 patients with SCFE associated with hypothyroidism in the literature, most SCFE occurred during puberty or in adults with delayed epiphyseal closure. Only two patients (4.8%), including the present patient, were ≤9 years old. Although being overweight or obese is common for patients with SCFE associated with hypothyroidism (76.0%), it was not observed in the present case. Persistent hypothyroidism, however, may be a risk factor for SCFE even before puberty and without obesity.

Successful Everolimus Treatment of Kaposiform Hemangioendothelioma With Kasabach-Merritt Phenomenon: Clinical Efficacy and Adverse Effects of mTOR Inhibitor Therapy.

Kasabach-Merritt phenomenon (KMP) is a life-threatening consumptive coagulopathy associated with underlying kaposiform hemangioendothelioma (KHE) in infancy. We describe the case of a 3-month-old girl with KHE complicated by KMP who responded dramatically to treatment with everolimus, a mechanistic target of rapamycin (mTOR) inhibitor. Immunohistochemical expression of mTOR was found in the KHE biopsy specimens, which may explain the improvement of KMP and reduction in KHE tumor size with mTOR inhibitor treatment. This effective use of everolimus may shed light on the emerging role of mTOR signaling in the development and pathogenesis of KHE and KMP.

Pilot intervention study of a low-salt diet with monomagnesium di-L-glutamate as an umami seasoning in psychiatric inpatients.

BACKGROUND: Schizophrenia patients have an elevated prevalence of stroke and cardiovascular risk factors, such as elevated body mass index, hypertension, and hyperlipidaemia. This pilot study investigated the influence of a low-sodium diet using umami seasoning on food intake and clinical parameters in schizophrenia patients. METHODS: A single-blind crossover intervention study was conducted in 15 clinical schizophrenia patients given a low-sodium diet with or without umami seasoning, monomagnesium di-L-glutamate, for 2 weeks. After the initial 2-week intervention, there was a 2-week washout period, and then the interventions were switched. Daily body weight, body mass index, abdominal circumference, blood pressure, and nutrient intake for each subject were determined. RESULTS: The results showed that subjects given monomagnesium di-L-glutamate had an approximately 25.9% reduction in dietary sodium. Furthermore, daily energy intake did not decrease, and no significant changes in body weight, body mass index, abdominal circumference, blood pressure, and nutrient intake were observed. CONCLUSIONS: The use of umami seasonings, such as monomagnesium di-L-glutamate, might be an effective long-term strategy for psychiatric patients requiring restricted sodium intake.

Loss-of-function polymorphisms in NQO1 are not associated with the development of subacute myelo-optico-neuropathy.

BACKGROUND: Subacute myelo-optico-neuropathy (SMON) is a neurological disorder associated with the administration of clioquinol, particularly at very high doses. Although clioquinol has been used worldwide, there was an outbreak of SMON in the 1950s-1970s in which the majority of cases were in Japan, prompting speculation that the unique genetic background of the Japanese population may have contributed to the development of SMON. Recently, a possible association between loss-of-function polymorphisms in NQO1 and the development of SMON has been reported. In this study, we analyzed the relationship between NQO1 polymorphisms and SMON in Japan. METHODS: We analyzed 125 Japanese patients with SMON. NQO1 loss-of-function polymorphisms (rs1800566, rs10517, rs689452, and rs689456) were evaluated. The allele frequency distribution of each polymorphism was compared between the patients and the healthy Japanese individuals (Human Genomic Variation Database and Integrative Japanese Genome Variation Database), as well as our in-house healthy controls. RESULTS: The frequencies of the loss-of-function NQO1 alleles in patients with SMON and the normal control group did not differ significantly. CONCLUSION: We conclude that known NQO1 polymorphisms are not associated with the development of SMON.

Differences in time-intensity sensory profiles of sweet taste intensity of glucose between older and young adults.

Background: To understand age-related changes in sweet taste perception in daily life, it is important to understand taste intensity at the suprathreshold level. Previous studies have attempted to characterize the temporal aspects of human taste perception in terms of time-intensity evaluations. The perception of dynamic taste intensity in older adults increases slowly for salty taste; however, there have been no previous studies on time-intensity sensory evaluation of sweet taste in older adults. We hypothesized that older adults perceive sweet taste intensity more slowly than young adults. Methods: Fifty young and 40 older adults participated in the study and glucose solutions of 0.6 M and 1.5 M were used as stimuli. The study comprised two experiments: (1) a cup tasting test (static taste perception in the mouth), and (2) a time-intensity sensory evaluation, in which the solutions were presented using a custom-made delivery system. The intra-oral device was made to fit each participant's dentition. Further, the level of gag reflex was taken into consideration for each participant in the design of the intra-oral device. A suction tube was placed across the posterior tongue near the throat to remove solution and saliva. The solution delivery system was controlled by an original computer program. Results: Older adults presented significantly different maximum intensity timing and slope for both concentrations compared with young adults (slope for 1.5 M, p < 0.01; others, p < 0.05). No significant differences were found between the older and young adults for reaction timing and maximum intensity. Conclusion: We conclude that older adults perceived sweetness more slowly than young adults, and ultimately perceived almost the same intensity as young adults. This is the first reported characterization of the time-intensity profile of sweet taste intensity of glucose in older adults. Using a standardized system enabled us to assess and compare feedback on taste intensities among different age groups in real-time. Based on this, we recommend older adults "savor" to perceive sweet tastes at the same level experienced by young adults.

Dentigerous cysts suspected the other odontogenic lesions on panoramic radiography and CT.

Dentigerous cysts are known as the second most common type of cyst in the jaws. The cyst is one of the lesions occurred frequently in the posterior body of the mandible and is often related to the unerupted third molar and forms around the crown of the unerupted tooth attaching at the cementoenamel junction. Such characteristic appearances are the diagnostic points differentiating from ameloblastoma or odontogenic keratocyst. However, it would be hard for us to diagnose it as a dentigerous cyst if the lesion does not show its typical appearance. We experienced two cases of dentigerous cysts which did not form around the crown of the unerupted tooth on radiologically. Both cysts were relatively large and resorbed adjacent teeth roots. Therefore, an ameloblastoma or an odontogenic keratocyst was suspected rather than a dentigerous cyst as the imaging diagnosis. The biopsy revealed that the lesion was a "dentigerous cyst" in one of the cases and "developmental cyst with inflammation" in another case. After the excision, the histopathological diagnosis was a dentigerous cyst with inflammation in both cases. This report shows the two cases of dentigerous cysts focusing on panoramic radiography and CT images. Also, we discuss the differential diagnosis by reconsidering those diagnostic points.

A PDE3A-SLFN12 Molecular Glue Exhibits Significant Antitumor Activity in TKI-Resistant Gastrointestinal Stromal Tumors.

PURPOSE: Gastrointestinal stromal tumor (GIST), the most common mesenchymal tumor with KIT or PDGFRA driver mutations, is typically treated with tyrosine kinase inhibitors (TKIs). However, resistance to TKIs due to secondary mutations is a common challenge in advanced GISTs. In addition, there are currently no effective therapies for several other molecular subtypes, such as SDH-deficient GISTs. Therefore, novel therapeutic strategies are needed. EXPERIMENTAL DESIGN: To address this need, we tested the efficacy of a novel non-TKI compound, OPB-171775, using patient-derived xenograft models of GISTs. In parallel, we sought to elucidate the mechanism of action of the compound. RESULTS: Our study revealed that OPB-171775 exhibited significant efficacy against GISTs regardless of their KIT mutation status by inducing complex formation between phosphodiesterase 3A (PDE3A) and Schlafen family member 12 (SLFN12), which are highly expressed in GISTs, leading to SLFN12 RNase-mediated cell death. Furthermore, we identified the activation of general control non-derepressible 2 (GCN2) and its downstream response as an effector pathway of SLFN12 in mediating anticancer activity and revealed potential pharmacodynamic markers. CONCLUSIONS: These findings suggest that OPB-171775, with its significant efficacy, could potentially serve as a novel and effective treatment option for advanced GISTs, particularly those resistant to TKIs.

[Relationship between birth month and corneal radius or axial length].

PURPOSE: Hyperopia prevalence is higher in children born in the autumn. This study attempted to detect whether corneal curvature or axial length are related to this phenomenon. METHODS: Using data from a total of 4056 cataract patients aged 40 and over from three medical facilities, corneal radius and axial length, measured to determine the intraocular lens power needed for cataract surgery, were reviewed. Mean corneal radius and mean axial length were calculated for each birth month. The means were then graphically analyzed to determine the relationship of corneal radius or axial length with birth month. RESULTS: No correlation was noted between axial length and birth month. However, a correlation between corneal radius and birth month was observed in each of the three facilities. Specifically, subjects born from October through December tended to have larger corneal radii. Numerically, the corneal radius showed a statistical relationship in terms of birth month (p < 0.001, ANOVA), while the axial length showed no relationship (p = 0.907, ANOVA). CONCLUSION: A statistically meaningful relationship between corneal curvature and birth month was detected. Corneal development might be affected by seasonal daylight variations in infancy, thus contributing to the occurrence of hyperopia.