A Case of Pontine Infarction due to Subclavian Steal Phenomenon Enhanced by an Arteriovenous Shunt for Hemodialysis.

We present a case of pontine infarction caused by subclavian steal phenomenon (SSP) due to subclavian artery stenosis (SAS) and an arteriovenous shunt in the forearm in a 74-year-old man with hemodialysis and stenting for SAS with improvement of SSP. He developed dysarthria during dialysis. He was admitted to our hospital and diagnosed with a pontine infarction. As the basilar artery appeared to be occluded on magnetic resonance angiography, an emergency diagnostic angiography was performed. Aortagram showed severe stenosis of the left subclavian artery. Right vertebral artery (VA) angiogram revealed retrograde arterial blood flow from the right VA to the left VA via the VA union, which suggested SSP. In addition, the steal was augmented by an ipsilateral hemodialysis arteriovenous shunt. Percutaneous subclavian artery stenting was performed 12 days later, and there was no recurrence of symptoms in the follow-up period. To our knowledge, this study is the first to report a patient with SSP who developed a pontine infarction due to SAS and an arteriovenous shunt during hemodialysis and who underwent subclavian artery stenting and had a good outcome.

Integrative analysis of Lunatic Fringe variants associated with spondylocostal dysostosis type-III.

Lunatic Fringe (LFNG) is required for spinal development. Biallelic pathogenic variants cause spondylocostal dysostosis type-III (SCD3), a rare disease generally characterized by malformed, asymmetrical, and attenuated development of the vertebral column and ribs. However, a variety of SCD3 cases reported have presented with additional features such as auditory alterations and digit abnormalities. There has yet to be a single, comprehensive, functional evaluation of causative LFNG variants and such analyses could unveil molecular mechanisms for phenotypic variability in SCD3. Therefore, nine LFNG missense variants associated with SCD3, c.564C>A, c.583T>C, c.842C>A, c.467T>G, c.856C>T, c.601G>A, c.446C>T, c.521G>A, and c.766G>A, were assessed in vitro for subcellular localization and protein processing. Glycosyltransferase activity was quantified for the first time in the c.583T>C, c.842C>A, and c.446C>T variants. Primarily, our results are the first to satisfy American College of Medical Genetics and Genomics PS3 criteria (functional evidence via well-established assay) for the pathogenicity of c.583T>C, c.842C>A, and c.446C>T, and replicate this evidence for the remaining six variants. Secondly, this work indicates that all variants that prevent Golgi localization also lead to impaired protein processing. It appears that the FRINGE domain is responsible for this phenomenon. Thirdly, our data suggests that variant proximity to the catalytic residue may influence whether LFNG is improperly trafficked and/or enzymatically dysfunctional. Finally, the phenotype of the axial skeleton, but not elsewhere, may be modulated in a variant-specific fashion. More reports are needed to continue testing this hypothesis. We anticipate our data will be used as a basis for discussion of genotype-phenotype correlations in SCD3.

A keyhole approach for intracranial hematoma removal using ORBEYE.

OBJECTIVE: By maximizing the advantages of exoscopy, we developed a keyhole approach for intracranial hematoma removal. Herein, we validated the utility of this procedure, and compared it with conventional microscopic hematoma removal and endoscopic hematoma removal in our institution. METHODS: We included 12 consecutive patients who underwent this procedure from June 2022 to March 2024. A 4-cm-long skin incision was made, and a keyhole craniotomy (diameter, 2.5 cm) was performed. An assistant manipulated a spatula, and an operator performed hematoma removal and hemostasis using typical microsurgical techniques under an exoscope. The dura mater was reconstructed without sutures using collagen matrix and fibrin glue. The outcomes of this series were compared with those of 12 consecutive endoscopic hematoma removals and 19 consecutive conventional microscopic hematoma removals from October 2018 to March 2024. RESULTS: The mean age was 72 ± 10 years, and seven (58%) patients were men. Hematoma location was the putamen in five patients and subcortical in seven patients. The mean operative time was 122 ± 34 min, the mean hematoma removal rate was 95% ± 8%, and the mortality rate was 0%. Although the preoperative hematoma volume was similar between the three groups, the operative time and total time in the operating room was significantly shorter in the exoscope group than the microscope group (P < 0.0001). CONCLUSION: This procedure may be simpler and faster than conventional microscopic hematoma removal, and comparable to endoscopic hematoma removal.

Lumbar Lordosis is a Risk Factor for Lumbar Catheter Fracture of Lumboperitoneal Shunt.

OBJECTIVE: This study aimed to investigate the causes of lumboperitoneal (LP) shunt failure and determine risk factors for lumbar catheter fracture. METHODS: We retrospectively investigated 149 patients who underwent LP shunting in our hospital between January 2012 and March 2023. Shunt reconstruction occurred in 22 patients (14.8%). Among these, cause of failure was lumbar catheter fracture in 5 (22.7%). Patient backgrounds, cause of LP shunt failure, surgical technique factors, and anatomical characteristics were extracted for comparative analysis and risk factors of lumbar catheter fracture were analyzed. RESULTS: Compared with the no reoperation group (n = 127), patients in the lumbar catheter fracture tended to be younger (63 ± 20 vs. 72 ± 11 years) and favorable neurologic status (modified Rankin scale score ≤2) after initial LP shunt; however, the differences were not significant. Lumbar lordosis was significantly higher in the lumbar catheter fracture group (52.7°± 14.8° vs. 37.1°± 12.3°; P = 0.0067). CONCLUSIONS: Excessive lumbar lordosis is a risk factor for lumbar catheter fracture in patients undergoing LP shunting. Younger age and higher level of postoperative activities of daily living might also be associated with lumbar catheter fracture.

Identification of a novel LFNG variant in a Chinese fetus with spondylocostal dysostosis and a systematic review.

Spondylocostal dysostosis (SCDO) encompasses a group of skeletal disorders characterized by multiple segmentation defects in the vertebrae and ribs. SCDO has a complex genetic etiology. This study aimed to analyze and identify pathogenic variants in a fetus with SCDO. Copy number variant sequencing and whole exome sequencing were performed on a Chinese fetus with SCDO, followed by bioinformatics analyses, in vitro functional assays and a systematic review on the reported SCDO cases with LFNG pathogenic variants. Ultrasound examinations in utero exhibited that the fetus had vertebral malformation, scoliosis and tethered cord, but rib malformation was not evident. We found a novel homozygous variant (c.1078 C > T, p.R360C) within the last exon of LFNG. The variant was predicted to cause loss of function of LFNG by in silico prediction tools, which was confirmed by an in vitro assay of LFNG enzyme activity. The systematic review listed a total of 20 variants of LFNG in SCDO. The mutational spectrum spans across all exons of LFNG except the last one. This study reported the first Chinese case of LFNG-related SCDO, revealing the prenatal phenotypes and expanding the mutational spectrum of the disorder.

A novel predictor of ischemic complications in the treatment of ruptured middle cerebral artery aneurysms: Neck-branching angle.

Objective: The risk factors of procedural cerebral ischemia (CI) in ruptured middle cerebral artery (MCA) aneurysms are unclear. This study proposed the neck-branching angle (NBA), a simple quantitative indicator of the aneurysm neck and branch vessels, and analyzed its usefulness as a predictor of procedural CI in ruptured MCA aneurysms. Methods: We retrospectively analyzed 128 patients with ruptured saccular MCA aneurysms who underwent surgical or endovascular treatment between January 2014 and June 2021. We defined the NBA as the angle formed by the MCA aneurysm neck and M2 superior or inferior branch vessel line. The superior and inferior NBA were measured on admission via three-dimensional computed tomography angiography on admission. We divided the patients into clipping (106 patients) and coiling (22 patients) groups according to the treatment. Risk factors associated with procedural CI were analyzed in each group. Results: Both groups showed that an enlarged superior NBA was a significant risk factor for procedural CI (clipping, P < 0.0005; coiling group, P = 0.007). The receiver operating characteristic curve showed the closed thresholds of the superior NBA with procedural CI in both groups (clipping group, 128.5°, sensitivity and specificity of 0.667 and 0.848, respectively; coiling group, 130.9°, sensitivity and specificity of 1 and 0.889, respectively). Conclusion: The NBA can estimate the procedural risk of ruptured MCA aneurysms. In addition, an enlarged superior NBA is a risk factor for procedural CI in both clipping and coiling techniques.

Automated volumetry of meningiomas in contrast-enhanced T1-Weighted MRI using deep learning.

BACKGROUND: Meningiomas are among the most common intracranial tumors. In these tumors, volumetric assessment is not only important for planning therapeutic intervention but also for follow-up examination.However, a highly accurate automated volumetric method for meningiomas using single-modality magnetic resonance imaging (MRI) has not yet been reported. Here, we aimed to develop a deep learning-based automated volumetry method for meningiomas in MRI and investigate its accuracy and potential clinical applications. METHODS: For deep learning, we used MRI images of patients with meningioma who were referred to Osaka University Hospital between January 2007 and October 2020. Imaging data of eligible patients were divided into three non-overlapping groups: training, validation, and testing. The model was trained and tested using the leave-oneout cross-validation method. Dice index (DI) and root mean squared percentage error (RMSPE) were measured to evaluate the model accuracy. Result: A total of 178 patients (64.6 ± 12.3 years [standard deviation]; 147 women) were evaluated. Comparison of the deep learning model and manual segmentation revealed a mean DI of 0.923 ± 0.051 for tumor lesions. For total tumor volume, RMSPE was 9.5 ± 1.2%, and Mann-Whitney U test did not show a significant difference between manual and algorithm-based measurement of the tumor volume (p = 0.96). CONCLUSION: The automatic tumor volumetry algorithm developed in this study provides a potential volume-based imaging biomarker for tumor evaluation in the field of neuroradiological imaging, which will contribute to the optimization and personalization of treatment for central nervous system tumors in the near future.

The Usefulness of Surgical Titanium Microclips for Mucosal Repair in the Frontal Sinus Using ORBEYE: A Technical Note.

Bifrontal craniotomy frequently involves opening the frontal sinus and mucosal injury. We report a new technique for mucosal repair in the frontal sinus using surgical titanium microclips. Six consecutive patients who underwent bifrontal craniotomy with frontal sinus exposure and mucosal injury underwent mucosal repair using surgical titanium microclips between April 2019 and August 2022. In all cases, the frontal sinus mucosa was peeled from the inner walls of the frontal sinus to ensure sufficient mucosal margin for clipping using ORBEYE. The repair was accomplished with the microclips in all cases. We also sealed the mucosal wound using fibrin glue and sufficiently filled the frontal sinus with bone debris, resulting in zero incidence of postoperative liquorrhea in all cases. Repairing the mucosa using surgical titanium microclips using ORBEYE may be a simple and quick technique when the frontal sinus mucosa is injured during craniotomy.

Survey of Guideline Compliance and Attitude Toward Symptom Management in Japanese Intensive Care Units.

Introduction: The Clinical Practice Guideline for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit (ICU) was revised in 2018 to include sleep disruption and immobility. Inadequate management of these symptoms can lead to negative consequences. A 2019 survey in Japan found that the guideline was recognized but needed to be consistently implemented. Objective: This study aimed to examine compliance with the guideline for symptom management of pain, agitation, delirium, and sleep in Japanese ICUs. Methods: This study included all ICUs in Japan and asked one representative from each unit to respond to the web survey from January 2022 to February 2022. Results: Of a potential 643 units, 125 respondents from the ICU were included in the analysis (19.4% response rate). Compared to the guideline's recommendations, (a) pain assessment was performed in 86.3% of patients who could self-report, and in 72.0% of those who could not self-report; (b) agitation and sedation assessment was performed in 99% of patients; (c) only 66.1% of nurses reported assessing sleep quality on the units, and 9.1% performed the subjective sleep quality assessment; (d) the use of the recommended risk factor of the delirium assessment tool was low (9.6%). Additionally, according to the survey respondents, contrary to the guideline, many units administered medications to prevent and treat delirium, and approximately 30% used multiple non-drug interventions. The data are expressed as numbers and percentages. Some datasets were incomplete due to missing values. Conclusion: Most units used drugs for delirium prevention and treatment, and only a few used non-drug interventions. There is a need to popularize the assessment of sleep and delirium risk factors and use non-drug interventions to promote patient-centered care in the future.

Second victim syndrome in intensive care unit healthcare workers: A systematic review and meta-analysis on types, prevalence, risk factors, and recovery time.

INTRODUCTION: Patient safety incidents, including medical errors and adverse events, frequently occur in intensive care units, leading to a significant psychological burden on healthcare workers. This burden results in second victim syndrome, which impacts the psychological and psychosomatic well-being of these workers. However, a systematic review focusing specifically on this condition among intensive care unit healthcare workers is lacking. Therefore, we aimed to conduct a systematic review and meta-analysis to examine the occurrence of second victim syndrome among intensive care unit healthcare workers, including the types, prevalence, risk factors, and recovery time associated with this condition. METHODS: We conducted a comprehensive search of the MEDLINE, CINAHL, PsycINFO, and Igaku Chuo Zasshi databases. The eligibility criteria encompassed retrospective, prospective, and cross-sectional studies and controlled trials, with no language restrictions. Data on the type, prevalence, risk factors, and recovery time of second victim syndrome were extracted and pooled. Prevalence estimates from the included studies were combined using a random-effects meta-analytic model. RESULTS: Of the 2,245 records retrieved, 16 potentially relevant studies were identified. Following full-text evaluation, five studies met the inclusion criteria and were included in the review. The findings revealed that 58% of intensive care unit healthcare workers experienced second victim syndrome. Frequent symptoms included guilt (12-68%), anxiety (38-63%), anger at self (25-58%), and lower self-confidence (7-58%). However, specific risk factors exclusive to intensive care unit healthcare workers were not identified in the review. Furthermore, approximately 20% of individuals took more than a year to recover or did not recover at all from the second victim syndrome. CONCLUSIONS: Thus, this condition is prevalent among intensive care unit healthcare workers and may persist for extended periods, potentially exceeding a year. The risk factors for second victim syndrome in the intensive care unit setting are unclear and require further investigation.

A resected case of acinar cell carcinoma of the pancreas with liver metastasis following chemotherapy using modified FOLFIRINOX.

BACKGROUND: Acinar cell carcinoma of the pancreas is a rare exocrine malignancy representing less than 1% of all pancreatic neoplasms. It has been reported that it responds to treatment differently from pancreatic ductal adenocarcinoma and the treatment algorithm for acinar cell carcinoma usually depends on the stage of the respective tumor and the patient's current status. CASE PRESENTATION: A 60-year-old man presented with upper abdominal pain and anorexia. Abdominal ultrasonography showed a large-sized hepatic mass and he was referred to our hospital. Contrast-enhanced computed tomography demonstrated a 110-mm low-density area occupying the right hemi-liver and an enhanced mass of 70 × 56 mm in the tail of the pancreas, which seemed to directly infiltrate into the spleen. The case was diagnosed as acinar cell carcinoma with a simultaneous liver metastasis identified by liver biopsy. Upfront resection of pancreatic cancer with distant metastasis might not be considered as an optimal choice, and in this case chemotherapy was administered prior to curative resection. Chemotherapy using the modified FOLFIRINOX regimen was undertaken, resulting in a partial remission; the liver tumor reduced in size from 110 to 47 mm and the pancreatic tumor from 70 to 40 mm. The patient then safely underwent curative hepatic resection with distal pancreato-splenectomy. Histological examinations revealed small-sized atypical cells with large nuclei that had formed acinar patterns, and immunostaining with trypsin was positive in tumor cells, which was in accordance with acinar cell carcinoma. More than 3 years later, the patient is doing well without any recurrence. CONCLUSION: Aggressive and curative surgery in combination with chemotherapy such as FOLFIRINOX could be a treatment option to achieve long-term survival in cases of acinar cell carcinoma with liver metastases.

Novel function of transglutaminase 2 in extracellular histone-induced acute lung injury.

Extracellular histones induce endothelial damage, resulting in lung haemorrhage; however, the underlying mechanism remains unclear. Factor XIII, as a Ca2+-dependent cross-linking enzyme in blood, mediates fibrin deposition. As another isozyme, transglutaminase 2 (TG2) has a catalytic activity distributing in most tissues. Herein, we investigated whether TG2 promotes fibrin deposition and mediates the adhesion of platelets to ECs in histone-induced acute lung injury (ALI). We evaluated the lung histology and the adhesion of platelets to endothelial cells (ECs) after injecting histones to wild-type (WT) C57BL/6J and TG2 knockout (TG2-/-) mice, and administered a TG2 inhibitor (NC9) to WT mice. Pulmonary haemorrhage was more severe in TG2-/- mice than that in WT mice. The area of fibrin deposition and the proportion of CD41+CD31+ cells were lower in TG2-/- mice than in WT mice. Pre-treatment of NC9 decreased the area of fibrin deposition and the proportion of CD41+CD31+ cells in WT mice. These results suggest that TG2 prevents from pulmonary haemorrhage in ALI by promoting the adhesion of platelets to ECs and the fibrin deposition.

Impact of postoperative complications on long-term survival in bladder cancer patients.

OBJECTIVE: To determine the impact of postoperative complications on long-term survival outcomes in patients with bladder cancer undergoing radical cystectomy. METHODS: This retrospective multi-institutional study included 766 bladder cancer patients who underwent radical cystectomy between 2011 and 2017. Patient characteristics, perioperative outcomes, all complications within 90 days after surgery and survival outcomes were collected. Each complication was graded based on the Clavien-Dindo system, and grouped using a standardized grouping method. The Comprehensive Complication Index, which incorporates all complications into a single formula weighted by their severity, was utilized. Overall survival and recurrence-free survival (local, distant or urothelial recurrences) were stratified by Comprehensive Complication Index (high: ≥26.2; low: <26.2). A multivariate model was utilized to identify independent prognostic factors. RESULTS: The incidence of any and major complications (≥Clavien-Dindo grade III) was 70 and 24%, respectively. In terms of Comprehensive Complication Index, 34% (261/766) of the patients had ≥26.2. Patients with Comprehensive Complication Index ≥ 26.2 had shorter overall survival (4-year, 59.5 vs. 69.8%, respectively, log-rank test, P = 0.0037) and recurrence free survival (51.9 vs. 60.1%, respectively, P = 0.0234), than those with Comprehensive Complication Index < 26.2. The Cox multivariate model identified the age, performance status, pT-stage, pN-stage and higher CCI (overall survival: HR = 1.35, P = 0.0174, recurrence-free survival: HR = 1.26, P = 0.0443) as independent predictors of both overall survivial and recurrence-free survival. CONCLUSIONS: Postoperative complications assessed by Comprehensive Complication Index had adverse effects on long-term survival outcomes. Physicians should be aware that major postoperative complications can adversely affect long-term disease control.

Switching mechanism from AR to EGFR signaling via 3-O-sulfated heparan sulfate in castration-resistant prostate cancer.

Androgen deprivation therapy is given to suppress prostate cancer growth; however, some cells continue to grow hormone-independently as castration-resistant prostate cancer (CRPC). Sulfated glycosaminoglycans promote ligand binding to receptors as co-receptors, but their role in CRPC remains unknown. Using the human prostate cancer cell line C4-2, which can proliferate in hormone-dependent and hormone-independent conditions, we found that epidermal growth factor (EGF)-activated EGFR-ERK1/2 signaling via 3-O-sulfated heparan sulfate (HS) produced by HS 3-O-sulfotransferase 1 (HS3ST1) is activated in C4-2 cells under hormone depletion. Knockdown of HS3ST1 in C4-2 cells suppressed hormone-independent growth, and inhibited both EGF binding to the cell surface and activation of EGFR-ERK1/2 signaling. Gefitinib, an EGFR inhibitor, significantly suppressed C4-2 cell proliferation and growth of a xenografted C4-2 tumor in castrated mouse. Collectively, our study has revealed a mechanism by which cancer cells switch to hormone-independent growth and identified the key regulator as 3-O-sulfated HS.

Maxillary labial peri-implant hard and soft tissue alteration observed on cross-sectional dimension: a 2-year prospective observational study.

OBJECTIVES: To evaluate how peri-implant hard and soft tissue height (BH, MH) alter after final prostheses placement related to labial hard and soft tissue thickness (BW, MW). MATERIALS AND METHODS: Forty-five platform-switched implants were classified into four groups according to BW and MW: type 1 (thick BW and thick MW), type 2 (thick BW and thin MW), type 3 (thin BW and thick MW), type 4 (thin BW and thin MW). Tissue resorption was evaluated on cone-beam CT images taken at final prostheses placement, at 1-year follow-up, and at 2-year follow-up. Kruskal-Wallis test and post hoc Mann-Whitney test were applied; significance was set to 0.05. RESULTS: BH resorption was 0.13 ± 0.12 mm in type 1, 0.26 ± 0.17 mm in type 2, 0.09 ± 0.09 mm in type 3, 0.94 ± 0.19 mm in type 4. Differences between type 1 and 4, type 2 and 4, and type 3 and 4 were statistically significant (p < 0.001, p = 0.005, p < 0.001, respectively). MH resorption was 0.10 ± 0.09 mm in type 1, 0.36 ± 0.16 mm in type 2, 0.12 ± 0.12 mm in Type 3, 0.79 ± 0.23 mm in type 4. Differences between type 1 and 2, type 1 and 4, type 2 and 3, type 2 and 4 and type 3 and 4 were statistically significant (p < 0.001). CONCLUSIONS: Significantly less BH/MH resorption occurs around implants with thick BW/MW than those with thin BW/MW in 2 years. Implants with thick peri-implant soft tissue resulted in significantly less tissue resorption in second year after final prostheses placement.

Mice lacking nucleotide sugar transporter SLC35A3 exhibit lethal chondrodysplasia with vertebral anomalies and impaired glycosaminoglycan biosynthesis.

SLC35A3 is considered an uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) transporter in mammals and regulates the branching of N-glycans. A missense mutation in SLC35A3 causes complex vertebral malformation (CVM) in cattle. However, the biological functions of SLC35A3 have not been fully clarified. To address these issues, we have established Slc35a3-/-mice using CRISPR/Cas9 genome editing system. The generated mutant mice were perinatal lethal and exhibited chondrodysplasia recapitulating CVM-like vertebral anomalies. During embryogenesis, Slc35a3 mRNA was expressed in the presomitic mesoderm of wild-type mice, suggesting that SLC35A3 transports UDP-GlcNAc used for the sugar modification that is essential for somite formation. In the growth plate cartilage of Slc35a3-/-embryos, extracellular space was drastically reduced, and many flat proliferative chondrocytes were reshaped. Proliferation, apoptosis and differentiation were not affected in the chondrocytes of Slc35a3-/-mice, suggesting that the chondrodysplasia phenotypes were mainly caused by the abnormal extracellular matrix quality. Because these histological abnormalities were similar to those observed in several mutant mice accompanying the impaired glycosaminoglycan (GAG) biosynthesis, GAG levels were measured in the spine and limbs of Slc35a3-/-mice using disaccharide composition analysis. Compared with control mice, the amounts of heparan sulfate, keratan sulfate, and chondroitin sulfate/dermatan sulfate, were significantly decreased in Slc35a3-/-mice. These findings suggest that SLC35A3 regulates GAG biosynthesis and the chondrodysplasia phenotypes were partially caused by the decreased GAG synthesis. Hence, Slc35a3-/- mice would be a useful model for investigating the in vivo roles of SLC35A3 and the pathological mechanisms of SLC35A3-associated diseases.

Collagen Network Formation in In Vitro Models of Musculocontractural Ehlers-Danlos Syndrome.

Loss-of-function mutations in carbohydrate sulfotransferase 14 (CHST14) cause musculocontractural Ehlers-Danlos syndrome-CHST14 (mcEDS-CHST14), characterized by multiple congenital malformations and progressive connective tissue fragility-related manifestations in the cutaneous, skeletal, cardiovascular, visceral and ocular system. The replacement of dermatan sulfate chains on decorin proteoglycan with chondroitin sulfate chains is proposed to lead to the disorganization of collagen networks in the skin. However, the pathogenic mechanisms of mcEDS-CHST14 are not fully understood, partly due to the lack of in vitro models of this disease. In the present study, we established in vitro models of fibroblast-mediated collagen network formation that recapacitate mcEDS-CHST14 pathology. Electron microscopy analysis of mcEDS-CHST14-mimicking collagen gels revealed an impaired fibrillar organization that resulted in weaker mechanical strength of the gels. The addition of decorin isolated from patients with mcEDS-CHST14 and Chst14-/- mice disturbed the assembly of collagen fibrils in vitro compared to control decorin. Our study may provide useful in vitro models of mcEDS-CHST14 to elucidate the pathomechanism of this disease.

Histories of Dermatan Sulfate Epimerase and Dermatan 4-O-Sulfotransferase from Discovery of Their Enzymes and Genes to Musculocontractural Ehlers-Danlos Syndrome.

Dermatan sulfate (DS) and its proteoglycans are essential for the assembly of the extracellular matrix and cell signaling. Various transporters and biosynthetic enzymes for nucleotide sugars, glycosyltransferases, epimerase, and sulfotransferases, are involved in the biosynthesis of DS. Among these enzymes, dermatan sulfate epimerase (DSE) and dermatan 4-O-sulfotranserase (D4ST) are rate-limiting factors of DS biosynthesis. Pathogenic variants in human genes encoding DSE and D4ST cause the musculocontractural type of Ehlers-Danlos syndrome, characterized by tissue fragility, joint hypermobility, and skin hyperextensibility. DS-deficient mice exhibit perinatal lethality, myopathy-related phenotypes, thoracic kyphosis, vascular abnormalities, and skin fragility. These findings indicate that DS is essential for tissue development as well as homeostasis. This review focuses on the histories of DSE as well as D4ST, and their knockout mice as well as human congenital disorders.

Cisplatin resistance driver claspin is a target for immunotherapy in urothelial carcinoma.

Bladder cancer is a major and fatal urological disease. Cisplatin is a key drug for the treatment of bladder cancer, especially in muscle-invasive cases. In most cases of bladder cancer, cisplatin is effective; however, resistance to cisplatin has a significant negative impact on prognosis. Thus, a treatment strategy for cisplatin-resistant bladder cancer is essential to improve the prognosis. In this study, we established a cisplatin-resistant (CR) bladder cancer cell line using an urothelial carcinoma cell lines (UM-UC-3 and J82). We screened for potential targets in CR cells and found that claspin (CLSPN) was overexpressed. CLSPN mRNA knockdown revealed that CLSPN had a role in cisplatin resistance in CR cells. In our previous study, we identified human leukocyte antigen (HLA)-A*02:01-restricted CLSPN peptide by HLA ligandome analysis. Thus, we generated a CLSPN peptide-specific cytotoxic T lymphocyte clone that recognized CR cells at a higher level than wild-type UM-UC-3 cells. These findings indicate that CLSPN is a driver of cisplatin resistance and CLSPN peptide-specific immunotherapy may be effective for cisplatin-resistant cases.

Growth risk classification and typical growth speed of convexity, parasagittal, and falx meningiomas: a retrospective cohort study.

OBJECTIVE: Meningiomas are the most common primary intracranial tumors, and their clinical and biological characteristics vary by location. Convexity, parasagittal, and falx meningiomas account for approximately 50%-65% of intracranial meningiomas. Focusing only on these locations, the aim of this study was to determine the typical speed of tumor growth, to assess the growth risk, and to show the possible tumor volume that many lesions can reach after 5 years. METHODS: Patients with radiologically suspected convexity, parasagittal, or falx meningiomas at the authors' institution were studied retrospectively. The relative growth rate (RGR) and annual volume change (AVC) were calculated from MRI at more than 3-month intervals. Based on sex, age, and signal intensity on T2-weighted MRI, the cases were classified into three groups: extremely high-growth, high-growth, and low-growth groups. RESULTS: The data of 313 cases were analyzed. The median RGR and AVC for this entire cohort were 6.1% (interquartile range [IQR] 2.4%-16.0%) and 0.20 (IQR 0.04-1.18) cm3/year, respectively. There were significant differences in sex (p = 0.018) and T2-weighted MRI signal intensity (p < 0.001) for RGR, and T2-weighted MRI signal intensity (p < 0.001), tumor location (p = 0.025), and initial tumor volume (p < 0.001) for AVC. The median RGR and AVC were 17.5% (IQR 8.3%-44.1%) and 1.05 (IQR 0.18-3.53) cm3/year, 8.2% (IQR 2.9%-18.6%) and 0.33 (IQR 0.06-1.66) cm3/year, and 3.4% (IQR 1.2%-5.8%) and 0.04 (IQR 0.02-0.21) cm3/year for the extremely high-growth, high-growth, and low-growth groups, respectively, with a significant difference among the groups (p < 0.001). A 2.24-times, or 5.24 cm3, increase in tumor volume over 5 years was typical in the extremely high-growth group, whereas the low-growth group showed little change in tumor volume even over a 5-year follow-up period. CONCLUSIONS: For the first time, the typical speed of tumor growth was calculated, focusing only on patients with convexity, parasagittal, and falx meningiomas. In addition, the possible tumor volume that many lesions in these locations can reach after 5 years was shown based on objective indicators. These results may allow clinicians to easily detect lesions that require frequent follow-up or early treatment by determining whether they deviate from the typical range of the growth rate, similar to a growth chart for children.