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Understanding the functions of human transcriptional regulatory genes SP110 and SP140 during Mycobacterium tuberculosis infection is crucial; in a mouse model, homologous genes Sp110 and Sp140 have been shown to negatively regulate inflammatory response genes, including the type I interferon (IFN) response. The reduction of these genes in mice is associated with susceptibility to M. tuberculosis infection and the development of necrotizing granulomatous lesions. To investigate the involvement of SP110 and SP140 in human inflammatory response, we analyzed their regulatory manner in THP-1 macrophages infected with M. tuberculosis . Genome-wide transcriptional profiling revealed that the depletion of SP110 and/or SP140 impaired the induction of gene expression associated with inflammatory responses, including IFN response genes, although it had little effect on the intracellular proliferation of M. tuberculosis . By contrast, genes related to phosphorylation were upregulated in infected macrophages with SP110 and/or SP140 knockdown, but downregulated in infected control macrophages without their knockdown. Reverse transcription-quantitative PCR and ELISA further confirmed the impairment of the induction of IFN response genes by the depletion of SP110 and/or SP140 in M. tuberculosis -infected macrophages. These findings suggest that human SP110 and SP140 act as positive regulators for genes associated with inflammatory responses in M. tuberculosis -infected macrophages., Importance: Tuberculosis (TB) is one of the most serious infectious diseases, with high morbidity and mortality worldwide. C3HeB/FeJ mice are widely utilized for evaluating anti-TB drugs because their drug sensitivity and pathology during M. tuberculosis infection resemble those of human TB, including the development of necrotizing granulomas. Downregulation of the transcriptional regulatory genes Sp110 and Sp140 in C3HeB/FeJ mice has been demonstrated to activate gene expression associated with inflammatory responses during M. tuberculosis infection, resulting in susceptibility to the infection. Here, we examined the regulatory manner of SP110 and SP140 using transcriptomic analysis in M. tuberculosis -infected human macrophages. Depletion of SP110 and/or SP140 in M. tuberculosis -infected THP-1 macrophages impaired the induction of gene expression associated with inflammatory responses, including interferon response genes, compared with that in control macrophages. These results suggest that human SP110 and SP140 act as positive regulators for genes associated with inflammatory responses upon M. tuberculosis infection.

A 26-year-old man presented with a tumor in the left soleus muscle. The tumor was diagnosed as a locally advanced leiomyosarcoma. The patient was treated with irradiation followed by wide resection. One year after surgery, the patient presented with multiple lung metastases. Despite aggressive sequential chemotherapy, systemic metastatic tumors continued to develop. To explore therapeutic options for the patient, we performed DNA-based CGP with FoundationOne ® CDx (F1). F1 identified an out-of-strand rearrangement of the NOS1AP::NTRK1 gene, which has not been previously reported. In contrast, RNA sequencing revealed an in-frame LMNA::NTRK1 gene, which is an oncogenic fusion gene.

Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC) occurs in 5-20% of TSC patients, with a subset developing hydrocephalus. We present a case of a 14-year-old male diagnosed with TSC in the neonatal period who developed SEGA and subsequent hydrocephalus. Despite reducing the tumor size with the mammalian target of rapamycin (mTOR) inhibitors, ventricular enlargement persisted, indicating that obstructive hydrocephalus due to the foramen of Monro blockage was not the sole mechanism. Elevated cerebrospinal fluid (CSF) protein levels suggested additional factors like impaired CSF outflow. This case underscores the need for comprehensive treatment strategies and further research to better understand and manage hydrocephalus in TSC patients with SEGA., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Nakamura et al.)

To elucidate the currently unknown molecular mechanisms responsible for the similarity and difference during the acquirement of resistance against gemcitabine (GEM) and paclitaxel (PTX) in patients with pancreatic carcinoma, we examined two-dimensional (2D) and three-dimensional (3D) cultures of parent MIA PaCa-2 cells (MIA PaCa-2-PA) and their GEM resistance cell line (MIA PaCa-2-GR) and PTX resistance (MIA PaCa-2-PR). Using these cells, we examined 3D spheroid configurations and cellular metabolism, including mitochondrial and glycolytic functions, with a Seahorse bio-analyzer and RNA sequencing analysis. Compared to the MIA PaCa-2-PA, (1) the formation of the 3D spheroids of MIA PaCa-2-GR or -PR was much slower, and (2) their mitochondrial and glycolytic functions were greatly modulated in MIA PaCa-2-GR or -PR, and such metabolic changes were also different between their 2D and 3D culture conditions. RNA sequencing and bioinformatic analyses of the differentially expressed genes (DEGs) using an ingenuity pathway analysis (IPA) suggested that various modulatory factors related to epithelial -mesenchymal transition (EMT) including STAT3, GLI1, ZNF367, NKX3-2, ZIC2, IFIT2, HEY1 and FBLX, may be the possible upstream regulators and/or causal network master regulators responsible for the acquirement of drug resistance in MIA PaCa-2-GR and -PR. In addition, among the prominently altered DEGs (Log2 fold changes more than 6 or less than -6), FABP5, IQSEC3, and GASK1B were identified as unique genes associated with their antisense RNA or pseudogenes, and among these, FABP5 and GASK1B are known to function as modulators of cancerous EMT. Therefore, the observations reported herein suggest that modulations of cancerous EMT may be key molecular mechanisms that are responsible for inducing chemoresistance against GEM or PTX in MIA PaCa-2 cells.

Despite continuing advances in the development of effective new therapies, including immunotherapies, the prognosis of pancreatic cancer remains extremely poor. Gap junction proteins have become attractive targets for potential cancer therapy. However, the role of gap junction beta-4 (GJB4) protein remains unexplored in pancreatic cancer. Through bioinformatic analyses we discovered pancreatic cancer tissues showed higher levels of GJB4 transcripts compared to normal pancreatic tissues and this had a negative effect on overall survival in patients that had pancreatic cancer. The high expression of nuclear GJB4 was identified as a negative prognostic factor in such patients. Knockdown of GJB4 in cultured pancreatic cancer cells resulted in G 0 /G 1 arrest followed by decreased cell proliferation and suppression of metastatic potential. The overexpression of GJB4 accelerated cell proliferation, migration, and invasion in a SUIT-2 cell line, whereas MET inhibitor canceled the acceleration. GJB4 suppression with siRNA significantly inhibited tumor growth in a mouse xenograft model. Mechanistically, suppression of GJB4 inhibited MET-AKT activities. Such data suggest that targeting the GJB4-MET axis could represent a promising new therapeutic strategy for pancreatic cancer., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

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., Competing Interests: None., (© 2024 The Authors. Published by Elsevier Inc.)

Whether organ-specific regeneration is induced by organ-specific endothelial cells (ECs) remains unelucidated. The formation of white matter lesions due to chronic cerebral hypoperfusion causes cognitive decline, depression, motor dysfunction, and even acute ischemic stroke. Vascular ECs are an important target for treating chronic cerebral hypoperfusion. Brain-derived ECs transplanted into a mouse chronic cerebral hypoperfusion model showed excellent angiogenic potential. They were also associated with reducing both white matter lesions and brain dysfunction possibly due to the high expression of neuroprotective humoral factors. The in vitro coculture of brain cells with ECs from several diverse organs suggested the function of brain-derived endothelium is affected within a brain environment due to netrin-1 and Unc 5B systems. We found brain CD157-positive ECs were more proliferative and beneficial in a mouse model of chronic cerebral hypoperfusion than CD157-negative ECs upon inoculation. We propose novel methods to improve the symptoms of chronic cerebral hypoperfusion using CD157-positive ECs., (© 2024. The Author(s).)

Myeloid differentiation factor 88 (MyD88), which is a key regulator of nuclear factor kappa B (NF-κB), plays an important role in tumorigenesis in lymphoid malignancies such as Waldenstrom's macroglobulinemia (WM). However, its biological function in multiple myeloma (MM), which is a malignant plasma cell disorder like WM, remains unexplored. In this article, we first demonstrated that higher expression MyD88 was significantly correlated with poor survival in patients with MM using multiple publicly available datasets. Interestingly, bioinformatic analysis also revealed that MyD88 gene alteration, which is recognized in nearly 80% of patients with WM, was extremely rare in MM. In addition, ST2825 (a specific inhibitor of MyD88) suppressed cell growth followed by apoptosis. Furthermore, ST2825 induced intracellular reactive oxygen species (ROS) in MM cells, and N-acetyl-l-cysteine, which is known as a ROS scavenger, significantly decreased the number of apoptotic MM cells evoked by ST2825 treatment. Taken together, our results indicated that ST2825 leads to ROS-dependent apoptosis in MM cells and could be an attractive therapeutic candidate for patients with MM. By highlighting the pathological mechanism of MyD88 in MM, this study also provides novel treatment strategies to conquer MM., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kohichi Takada reports financial support was provided by Daiichi Sankyo., (© 2024 The Authors.)

Background and Purpose: There has been limited literature regarding the bridging veins (BVs) of the medulla oblongata around the foramen magnum (FM). The present study aims to analyze the normal angioarchitecture of the BVs around the FM using slab MIP images of three-dimensional (3D) angiography., Methods: We collected 3D angiography data of posterior fossa veins and analyzed the BVs around the FM using slab MIP images. We analyzed the course, outlet, and number of BVs around the FM. We also examined the detection rate and mean diameter of each BV., Results: Of 57 patients, 55 patients (96%) had any BV. The median number of BVs was two (range: 0-5). The BVs originate from the perimedullary veins and run anterolaterally to join the anterior condylar vein (ACV), inferior petrosal sinus, sigmoid sinus, or jugular bulb, inferolaterally to join the suboccipital cavernous sinus (SCS), laterally or posterolaterally to join the marginal sinus (MS), and posteriorly to join the MS or occipital sinus. We classified BVs into five subtypes according to the draining location: ACV, jugular foramen (JF), MS, SCS, and cerebellomedullary cistern (CMC). ACV, JF, MS, SCS, and CMC BVs were detected in 11 (19%), 18 (32%), 32 (56%), 20 (35%), and 16 (28%) patients, respectively. The mean diameter of the BVs other than CMC was 0.6 mm, and that of CMC BV was 0.8 mm., Conclusion: Using venous data from 3D angiography, we detected FM BVs in most cases, and the BVs were connected in various directions., (© 2023. The Author(s).)

The occurrence of early brain injury (EBI) following subarachnoid hemorrhage (SAH) is crucial in the prognosis of SAH; however, no effective treatment for EBI has been developed. Gut microbiome (GM) composition influences the outcome of various diseases, including ischemic stroke. Here, we evaluated whether prior GM alteration could prevent EBI following SAH. We altered the GM of 7-week-old male rats by administering antibiotic-containing water for 2 weeks and performing fecal microbiome transplantation after antibiotic induction. Composition of the GM was profiled using 16S rRNA. We induced SAH by injecting blood in the subarachnoid space of control rats and rats with altered GM. We evaluated EBI indicators such as neurological score, brain water content, Evans blue extravasation, and neuronal injury. Additionally, we studied inflammatory cells using immunohistochemistry, immunocytochemistry, quantitative PCR, and flow cytometry. EBI was significantly averted by alterations in GM using antibiotics. The altered GM significantly prevented neutrophil infiltration into the brain among inflammatory cells, and this anti-inflammatory effect was observed immediately following SAH onset. The altered GM also prevented neutrophil extracellular trap formation in the brain and blood, indicating the systemic protective effect. The cause of the protective effect was attributed to a significant decrease in aged neutrophils (CXCR4 high CD62L low ) by the altered GM. These protective effects against EBI disappeared when the altered GM was recolonized with normal flora. Our findings demonstrated that EBI following SAH is associated with GM, which regulated neutrophil infiltration., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Accumulating evidence has demonstrated platinum-based chemotherapy followed by maintenance therapy with a poly Adenosine diphosphate (ADP)-ribose polymerase inhibitor (olaparib) show benefits in unresectable pancreatic cancer with a germline (g)BRCA1/2 mutation. Evaluation of the germline BRCA1 and BRCA2 mutation is essential for making decisions on a treatment strategy for patients with unresectable pancreatic cancer. However, the detection rates of germline BRCA1 and BRCA2 mutations and efficacy of maintenance with olaparib remain undetermined, prospectively, in Japan., Methods & Results: In this prospective analysis, the rate of germline BRCA1 and BRCA2 mutations and efficacy of chemotherapy were analyzed in 136 patients with pancreatic cancer who underwent BRACAnalysis® (85 patients) or FoundationOne® CDx (51 patients) between January 2020 and July 2022. A total of six patients (4.4%) had a germline BRCA1 and BRCA2 mutation. Five patients were treated with modified FOLFIRINOX and one with fluorouracil and oxaliplatin. All patients continued platinum-based chemotherapy for ˃4 months and were subsequently treated with olaparib as a maintenance therapy. The response rate to platinum-based chemotherapy in the germline BRCA1 and BRCA2 mutation-positive group was significantly better than that of the germline BRCA1 and BRCA2 mutation-negative group (66% vs 23%, P = 0.04). All patients harbouring a germline BRCA1 and BRCA2 mutation were able to switch to olaparib. The median progression-free survival using olaparib was 5.7 months (range 3.0-9.2)., Conclusions: The rate of germline BRCA1 and BRCA2 mutations found in patients with unresectable pancreatic cancer was comparable to those of previous studies.An analysis of germline BRCA1 and BRCA2 mutations has benefits for all patients with unresectable pancreatic cancer with regard to decisions on therapeutic strategies in a clinical practice setting., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Overexpression of inhibitor of apoptosis (IAP) proteins is associated with poor prognosis. In multiple myeloma (MM), the IAP inhibitors (IAPi), LCL161, have been evaluated in preclinical and clinical settings but are not fully effective. Among IAPs, XIAP has the strongest anti-apoptotic function with direct binding activity to caspases and cIAP1 and cIAP2 are positive regulator of NF-κB signaling. Prior IAPi such as LCL161 has high affinity to cIAP1 and cIAP2 resulting in inferior inhibiting activity against XIAP. A novel dimeric IAPi, AZD5582 (C 58 H 78 N 8 O 8 ), have high binding potency to XIAP with EC50 dose of 15 nM, enabling to simultaneous inhibit XIAP and cIAP1/2. AZD5582 monotherapy showed cell growth inhibition for all MM cell lines, MM1S, RPMI8226, U266 and KMS-5 and induced apoptosis. AZD5582 further showed anti-proliferation effect under the IL-6 additional condition and inhibited JAK-STAT signaling triggered by IL-6. AZD5582 combined with carfilzomib therapy showed a synergistic effect. Enhanced apoptosis was also observed in combination therapy. Synergistic effect was further observed with other conventional therapeutics. Simultaneous XIAP and cIAP1/2 inhibition by the dimeric IAPi AZD5582 is promising. This study provides a rationale of AZD5582 as a new treatment strategy in monotherapy and in combination therapy., Competing Interests: Declaration of competing interest The authors declare they have no conflict of interest to disclose., (Copyright © 2023 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Cerebral organoids (COs) are derived from human-induced pluripotent stem cells in vitro and mimic the features of the human fetal brain. The development of COs is largely dependent on "self-organization" mechanisms, in which differentiating cells committed to cortical cells autonomously organize into the cerebral cortex-like tissue. However, extrinsic manipulation of their morphology, including size and thickness, remains challenging. In this study, we discovered that silicate microfiber scaffolds could support the formation of cortical neuronal layers and successfully generated cortical neuronal layers, which are 9 times thicker than conventional COs, in 70 days. These cortical neurons in the silicate microfiber layer were differentiated in a fetal brain-like lamination pattern. While these cellular characteristics such as cortical neurons and neural stem/progenitor cells were like those of conventional COs, the cortical neuronal layers were greatly thickened in sheet-like configuration. Moreover, the cortical neurons in the scaffolds showed spontaneous electrical activity. We concluded that silicate microfiber scaffolds support the formation of the cortical neuronal layers of COs without disturbing self-organization-driven corticogenesis. The extrinsic manipulation of the formation of the cortical neuronal layers of COs may be useful for the research of developmental mechanisms or pathogenesis of the human cerebral cortex, particularly for the development of regenerative therapy and bioengineering., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Due to the lack of studies, the long-term prognoses of unfit patients with gastric cancer (GC) who did not receive any aggressive cancer treatment (best supportive care [BSC] cases) remain unclear, especially for those with potentially curable GC. We conducted this observational study to capture the real-world data of characteristics and outcomes for BSC cases., Method: Consecutive clinical records of patients with GC diagnosed at Steel Memorial Muroran Hospital from January 2017 to December 2021 were analyzed., Result: Of 481 patients diagnosed with GC, 91 (18.9%) were BSC cases. The median overall survival (OS) was 12.4, 8.3, and 2.5 months for clinical stage (cStage) I, II-III, and IV, respectively. Patients with potentially curable GC (cStage I-III) had significantly longer OS than those with incurable disease (cStage IV), with a hazard ratio for death of 0.29 (95% confidence interval: 0.18-0.47)., Conclusion: Our report provides useful information for decision-making for unfit patients with GC in daily clinical practice., Competing Interests: K.T. received lecture fees from Eisai, Janssen, Chugai, Ono, Otsuka, Daiichi Sankyo, and Sanofi. The remaining authors declare that they have no known competing financial interests that might affect the research reported in this article., (© Yohei Arihara et al., 2023; Published by Mary Ann Liebert, Inc.)

Objectives: The usefulness of 0.6% sodium alginate (SA) as a submucosal (SM) injection solution for endoscopic SM dissection (ESD) has gained attention over the past few years. However, using ESD for colorectal neoplastic lesions is not explicitly researched as yet. Thus, we conducted this study to determine the feasibility and safety of 0.6% SA solution for colorectal ESD., Methods: In this single-center, retrospective pilot study, a total of 100 cases treated with ESD using 0.6% SA as a SM injection solution for colorectal neoplasia at our institute were retrospectively reviewed to clarify the clinical feasibility and safety of 0.6% SA. The primary endpoint was to evaluate the complication rate, and the secondary endpoint was to determine the procedure time and the amount of solution used., Results: Intraoperative perforation was observed in 1 case (1.0%), 2 cases (2.0%) presented with postprocedural hemorrhage, and no lethal adverse events were observed. The median ESD procedure times were 39.5 min (10-150), and the amount of solution used was less than 20 mL in 67 cases (67.0%). En-bloc resection could be achieved in 97 cases (97.0%). Although six cases underwent subsequent surgery due to the deep SM invasion (>1000 μm), there were no cases with nodal involvement, confirmed through histopathological evaluation., Conclusions: Our findings indicate that 0.6% SA can potentially ensure safe and secure ESD for colorectal neoplasia., Competing Interests: Authors declare no conflicts of interests for this article., (© 2023 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Although the six-transmembrane epithelial antigen of prostate 1 (STEAP1) was first identified in advanced prostate cancer, its overexpression is recognized in multiple types of cancer and associated with a poor prognosis. STEAP1 is now drawing attention as a promising therapeutic target because of its tumor specificity and membrane-bound localization. The clinical efficacy of an antibody-drug conjugate targeting STEAP1 in metastatic, castration-resistant, prostate cancer was demonstrated in a phase 1 trial. Furthermore, growing evidence suggests that STEAP1 is an attractive target for immunotherapies such as chimeric antigen receptor-T cell therapy. In this review, we summarize the oncogenic functions of STEAP1 by cancer type. This review also provides new insights into the development of new anticancer strategies targeting STEAP1., Competing Interests: KT received lecture fee from Daiichi Sankyo. 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 Nakamura, Arihara and Takada.)

Background: Elevated albumin-free or unbound bilirubin (UB) levels beyond the first week of life have been associated with the development of bilirubin encephalopathy in preterm infants. However, the mechanism(s) that induces this prolonged unbound bilirubinemia has remained unknown. We hypothesized that it may due to a sustained lower bilirubin-binding affinity of albumin in extremely premature infants., Methods: Twenty-two very preterm infants born at 28-31 weeks' gestational age (GA) (VPT Group) and 21 extremely preterm infants born at 22-27 weeks' GA (EPT Group) were retrospectively studied. On days 14, 21, and 28, bilirubin-binding affinity of albumin was assessed by calculating of the UB/total bilirubin ratio, bilirubin-albumin molar ratio (BAMR), and binding affinity (Ka)., Results: On days 14, 21, and 28, significantly higher UB/total bilirubin ratios were found in the EPT than in the VPT Group. Although BAMRs were comparable, significantly lower Ka values on days 14, 21, and 28 were observed in the EPT than those in the VPT Group (56.1 vs. 70.9 L/μmol, p < 0.001; 55.2 vs. 74.7 L/μmol, p < 0.001; 53.0 vs. 86.5 L/μmol, p < 0.001, respectively)., Conclusions: EPT infants have a sustained lower bilirubin-binding affinity of albumin beyond the first week of life., Impact: Bilirubin encephalopathy is still reported in extremely preterm (EPT) infants. EPT infants often have prolonged unbound bilirubinemia beyond the first week of life. Sustained lower bilirubin-binding affinity of albumin, regardless of the bilirubin-albumin molar ratio (BAMR), is observed in EPT infants. BAMRs should not be used as a surrogate marker of unbound bilirubinemia, especially in EPT infants at a later postnatal period., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Multiple myeloma (MM) is a cancer characterized by the expansion of plasma cells in the bone marrow. Survival times of patients with MM have increased due to the development of novel therapeutic agents. We herein highlight three MM cases that had a poor prognosis despite treatment with novel therapeutic agents. Of note, all patients presented with hyperammonemia that led to a consciousness disorder. The outcome for patients with MM showing high levels of serum ammonia continues to be poor, even with the use of novel therapies. For such patients showing a consciousness disorder, hyperammonemia should be considered as a possible cause.

A 75-year-old man with a history of distal gastrectomy for gastric cancer at 48 years of age underwent abdominal computed tomography, which revealed a left hepatic lobe tumor alongside direct gastric invasion. His blood test results revealed significant increase in serum alpha-fetoprotein (AFP) levels (32240.3ng/mL). A gastroscopy revealed that the histopathological findings of the biopsy specimens of the gastric invasion area were identical to those observed in the surgical specimens of gastric cancer, which was diagnosed 27 years earlier. The evaluation of the biopsy and surgical specimens revealed AFP positivity, which confirmed the diagnosis of the late recurrence of AFP-positive gastric cancer. Herein, we presented a rare clinical case of this malignancy. Additionally, a close, long-term postoperative follow-up is warranted in patients with AFP-producing gastric cancer.

Objective: Intracranial atherosclerosis disease (ICAD) is one of the most common causes of acute ischemic stroke. In endovascular treatment (EVT) for acute large vessel occlusion stroke-related ICAD, reocclusion of the recanalized artery due to in situ thrombosis is problematic. In this study, the safety and efficacy of prasugrel administration to avoid reocclusion of emergent EVT for ICAD was investigated., Methods: All consecutive emergent EVTs for ICAD between September 2019 and December 2022 were included in this study. The procedures were divided into two groups as receiving periprocedural prasugrel ( PSG group ) or not ( non-PSG group ). Target vessel patency on follow-up, postprocedural intracranial hemorrhage (ICH), and clinical outcome were compared between PSG and non-PSG groups., Results: A total of 27 procedures were included in this analysis. Nineteen target vessels were patent on follow-up and eight were non-patent. Fifteen patients received prasugrel (18.75 mg: 11 cases, 11.25 mg: 4 cases), and twelve patients did not receive prasugrel. The target vessel patency rate was better in the PSG group vs. non-PSG group (100% vs. 33.3%, respectively; p = 0.0002). The postprocedural ICH rate was not different between the groups (PSG: 40.0% vs. non-PSG: 25.0%; p = 0.68), and all ICHs were asymptomatic. Good clinical outcome (modified Rankin Scale score of 0 to 3 at discharge) was more frequent in the PSG group than that in the non-PSG group (66.7% vs. 16.7%, respectively; p = 0.019)., Conclusion: Prasugrel administration was significantly associated with target vessel patency and good clinical outcome after emergent EVT for ICAD without increasing the symptomatic ICH rate. Prasugrel administration might be safe and effective to avoid reocclusion during and after emergent EVT for ICAD., Competing Interests: The authors declare that they have no conflicts of interest., (©2023 The Japanese Society for Neuroendovascular Therapy.)

We herein report a rare case of unresectable liposarcoma that showed a complete response to eribulin. Furthermore, a low expression of phosphorylated AKT (p-AKT) on an immunohistological evaluation was observed. This result is consistent with our previous preclinical study that demonstrated the significance of p-AKT signaling for eribulin resistance in multiple subtypes of soft tissue sarcoma (STS) cells. This case highlights the potential benefits of eribulin as well as the mechanism underlying resistance to eribulin in patients with unresectable or metastatic STS, especially liposarcoma.

Background: Anterior chest wall arteriovenous graft (ACWAVG) is one option for haemodialysis patients when vessels of the upper extremities become exhausted. We report here the long-term outcomes of ACWAVG with polyurethane., Methods: From April 2005 to October 2015, nine ACWAVGs with polyurethane grafts were created. We observed patients until April 2019 and evaluated graft patency, interval from operation to first cannulation, and numbers of interventions and complications., Results: Primary patency rate and secondary patency rate of 6, 12 and 24 months were 55.3%, 33.3%, 33.3% and 77.8%, 55.6%, 55.6% respectively. Mean interval from operation to first cannulation was 3 days. Infection rate and kinking formation rate were slightly higher than previous reports of ACWAVGs with expanded polytetrafluoroethylene (ePTFE). However, one patient was able to keep using a single graft for 166 months with multiple interventions., Conclusions: Slight disadvantage are seen with patency rate and complication rate in polyurethane ACWAVG compare to ePTFE. However, when early cannulation is required, polyurethane is worth to consider for creating ACWAVG.

Background and Objectives: Intracranial artery stenosis is the predominant etiology of ischemic stroke in the Asian population. Furthermore, the presence of the RNF213 p.R4810K variant, which is a susceptibility gene for moyamoya disease, increases the risk of ischemic stroke attributable to large-artery atherosclerosis. Accordingly, we hypothesized that this genetic variant may affect the long-term outcome of intracranial artery stenosis in the East Asian population. We thus aimed to examine the effect of this variant on the long-term progression and prognosis of intracranial artery stenosis., Methods: Using a prospective database, we identified adult patients with intracranial artery stenosis who underwent periodic MRI examinations for >5 years. We evaluated stenosis progression using a validated visual grading system. We excluded patients diagnosed with moyamoya disease at the time of initial MRI. Genotyping of RNF213 p.R4810K was performed at the end of the follow-up period., Results: Among 52 eligible patients, 22 (42%) were carriers of the RNF213 p.R4810K variant. The median follow-up duration was 10.3 years. During the follow-up period, progression of intracranial artery stenosis was observed in 64% variant carriers and 27% noncarriers. There was a significant association of the variant with time to progression of intracranial artery stenosis (hazard ratio [HR] 3.31, 95% CI 1.38-7.90, p = 0.007), and time to the composite endpoint of symptomatic stroke and transient ischemic attack (HR 3.70, 95% CI 1.15-11.86, p = 0.028), but not to symptomatic stroke alone (HR 2.18, 95% CI 0.62-7.74, p = 0.23). Two variant carriers with progression were newly diagnosed with moyamoya disease., Discussion: Our findings indicated that the RNF213 p.R4810K variant increases the risk of intracranial artery stenosis progression., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Infection with Mycobacterium tuberculosis leads to the development of tuberculosis (TB) with the formation of granulomatous lesions. Foamy macrophages (FM) are a hallmark of TB granulomas, because they provide the primary platform of M. tuberculosis proliferation and the main source of caseous necrosis. In this study, we applied spatial multiomic profiling to identify the signatures of FM within the necrotic granulomas developed in a mouse model resembling human TB histopathology. C3HeB/FeJ mice were infected with M. tuberculosis to induce the formation of necrotic granulomas in the lungs. Using laser microdissection, necrotic granulomas were fractionated into three distinct regions, including the central caseous necrosis, the rim containing FM, and the peripheral layer of macrophages and lymphocytes, and subjected to proteomic and transcriptomic analyses. Comparison of proteomic and transcriptomic analyses of three distinct granulomatous regions revealed that four proteins/genes are commonly enriched in the rim region. Immunohistochemistry confirmed the localization of identified signatures to the rim of necrotic granulomas. We also investigated the localization of the representative markers for M1 macrophages in granulomas because the signatures of the rim included M2 macrophage markers. The localization of both macrophage markers suggests that FM in necrotic granulomas possessed the features of M1 or M2 macrophages. Gene set enrichment analysis of transcriptomic profiling revealed the upregulation of genes related to M2 macrophage activation and mTORC1 signaling in the rim. These results will provide new insights into the process of FM biogenesis, leading to further understanding of the pathophysiology of TB granulomas., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Seto, Nakamura, Guo, Hikichi, Wakabayashi, Miyabayashi, Nagata, Hijikata and Keicho.)

Characterization of the genomic landscape of biliary tract cancer (BTC) may lead to applying genotype-matched therapy for patients with this disease. Evidence that comprehensive cancer genomic profiling (CGP) guides genotype-matched therapy to improve clinical outcomes is building. However, the significance of CGP in patients with BTC remains unclarified in clinical practice. Therefore, the purposes of this study were to assess the utility of CGP and identify associations between clinical outcomes and genomic alterations in patients with BTC. In this prospective analysis, detection rates for actionable genomic alterations and access rates for genotype-matched therapy were analyzed in 72 patients with advanced BTC who had undergone commercial CGP. Cox regression analyses assessed relationships between overall survival and genomic alterations detected with CGP. The most common genomic alterations detected were TP53 (41, 56.9%), followed by CDKN2A/B (24, 33.3%/20, 27.8%), and KRAS (20, 27.8%). Actionable genomic alterations were identified in 58.3% (42/72) of patients. Detection rates for FGFR2 fusions, IDH1 mutations, and BRAF V600E were low in this cohort. Eight (11.1%) patients received genotype-matched therapy. For patients with intrahepatic cholangiocarcinoma (ICC), CDKN2A/B loss was associated with shorter overall survival. These real-world data demonstrate that CGP can identify therapeutic options in patients with advanced BTC. CDKN2A/B loss was identified as a poor prognostic factor in patients with ICC. Thus, this study provides a rationale for considering CGP in planning therapeutic strategies for advanced BTC., Competing Interests: YK received a research grant from Takeda Pharmaceutical Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Takada, Kubo, Kikuchi, Yoshida, Murota, Arihara, Nakamura, Nagashima, Tanabe, Sugita, Tanaka, Miura, Ohhara, Ishiguro, Yokouchi, Kawamoto, Mizukami, Ohnishi, Kinoshita and Sakurai.)

The establishment of animal models reflecting human Mycobacterium avium complex (MAC) lung disease (LD) pathology has the potential to expand our understanding of the disease pathophysiology. However, inducing sustained infection in immunocompetent mice is difficult since MAC generally shows less virulence and higher genetic variability than M. tuberculosis. To overcome this hurdle, we developed a screening system for identifying virulent MAC strains using whole-genome sequencing (WGS). We obtained nine clinical strains from Mycobacterium avium complex lung disease (MAC-LD) patients and divided them into two groups to make the mixed strain inocula for infection. Intranasal infection with the strain mixture of both groups in BALB/c mice resulted in progressive infection and extensive granuloma formation in the lungs, suggesting the existence of highly pathogenic strains in each group. We hypothesized that the change in the abundance of strain-specific single-nucleotide variants (SNVs) reflects the change in bacterial number of each strain in infected lungs. Based on this hypothesis, we quantified individual strain-specific SNVs in bacterial DNA from infected lungs. Specific SNVs for four strains were detected, suggesting the pathogenicity of these four strains. Consistent with these results, individual infection with these four strains induced a high lung bacterial burden, forming extensive peribronchial granuloma, while the other strains showed a decreased lung bacterial burden. The current method combining mixed infection and WGS accurately identified virulent strains that induced sustained infection in mice. This method will contribute to the establishment of mouse models that reflect human MAC-LD and lead to antimycobacterial drug testing. IMPORTANCE To promote research on Mycobacterium avium complex (MAC) pathogenicity, animal models reflecting human progressive MAC lung disease (MAC-LD) are needed. Because there is high genetic and virulence diversity among clinical MAC strains, choosing a suitable strain is an important process for developing a mouse model. In this study, we developed a screening system for virulent strains in mice by combining mixed infection and whole-genome sequencing analysis. This approach is designed on the hypothesis that in vivo virulence of MAC strains can be examined simultaneously by comparing changes in the abundance of strain-specific single-nucleotide variants in the mouse lungs after infection with mixed strains. The identified strains were shown to induce high bacterial burdens and cause extensive peribronchial granuloma resembling the pulmonary pathology of human MAC-LD. The current method will help researchers develop mouse models that reflect human MAC-LD and will lead to further investigation of MAC pathogenicity.

Background and Purpose: Environmental factors are important with respect to the rupture of cerebral aneurysms. However, the relationship between the gut microbiome, an environmental factor, and aneurysm rupture is unclear. Therefore, we compared the gut microbiome in patients with unruptured intracranial aneurysms (UIAs) and ruptured aneurysms (RAs) to identify the specific bacteria causing the rupture of cerebral aneurysms., Methods: A multicenter, prospective case-control study was conducted over one year from 2019 to 2020. The fecal samples of patients with stable UIAs and RAs immediately after onset were collected. Their gut microbiomes were analyzed using 16S rRNA sequencing. Subsequently, a phylogenetic tree was constructed, and polymerase chain reaction was performed to identify the specific species., Results: A total of 28 RAs and 33 UIAs were included in this study. There was no difference in patient characteristics between RAs and UIAs: age, sex, hypertension, dyslipidemia, diabetes status, body mass index, and smoking. No difference was observed in alpha diversity; however, beta diversity was significantly different in the unweighted UniFrac distances. At the phylum level, the relative abundance of Campylobacter in the RA group was larger than that in the UIA group. Furthermore, the gut microbiome in the RA and UIA groups exhibited significantly different taxonomies. However, Campylobacter was focused on because it is widely known as pathogenic among these bacteria. Then, a phylogenetic tree of operational taxonomic units related to Campylobacter was constructed and 4 species were identified. Polymerase chain reaction for these species identified that the abundance of the genus Campylobacter and Campylobacter ureolyticus was significantly higher in the RA group., Conclusions: The gut microbiome profile of patients with stable UIAs and RAs were significantly different. The genus Campylobacter and Campylobacter ureolyticus may be associated with the rupture of cerebral aneurysms.

Background: Thrombosis is a dynamic process, and a thrombus undergoes physical and biochemical changes that may alter its response to reperfusion therapy. This study assessed whether thrombus age influenced reperfusion quality and outcomes after mechanical thrombectomy for cerebral embolism., Methods: We retrospectively evaluated 185 stroke patients and thrombi that were collected during mechanical thrombectomy at three stroke centers. Thrombi were pathologically classified as fresh or older based on their granulocytes' nuclear morphology and organization. Thrombus components were quantified, and the extent of NETosis (the process of neutrophil extracellular trap formation) was assessed using the density of citrullinated histone H3-positive cells. Baseline patient characteristics, thrombus features, endovascular procedures, and functional outcomes were compared according to thrombus age., Results: Fresh thrombi were acquired from 43 patients, and older thrombi were acquired from 142 patients. Older thrombi had a lower erythrocyte content ( p  < 0.001) and higher extent of NETosis ( p  = 0.006). Restricted mean survival time analysis revealed that older thrombi were associated with longer puncture-to-reperfusion times (difference: 15.6 minutes longer for older thrombi, p  = 0.002). This association remained significant even after adjustment for erythrocyte content and the extent of NETosis (adjusted difference: 10.8 minutes, 95% confidence interval [CI]: 0.6-21.1 minutes, p  = 0.039). Compared with fresh thrombi, older thrombi required more device passes before reperfusion ( p  < 0.001) and were associated with poorer functional outcomes (adjusted common odds ratio: 0.49; 95% CI: 0.24-0.99)., Conclusion: An older thrombus delays reperfusion after mechanical thrombectomy for ischemic stroke. Adding therapies targeting thrombus maturation may improve the efficacy of mechanical thrombectomy., Competing Interests: Dr. Kitano reports lecture fees from Stryker. Dr. Nakamura reports lecture fees from Johnson & Johnson, Medtronic, and Stryker. Dr. Todo reports lecture fees from Medtronic. The other authors have no conflicts relevant to the contents of this article to disclose., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Colonic anisakiasis is rare because most cases of anisakiasis occur in the stomach. An accurate diagnosis is sometimes difficult because of the rarity and symptom nonspecificity. We should consider the possibility of colonic anisakiasis when examining patients who have a history of consuming raw fish., Competing Interests: The authors state that they have no conflict of interest., (© 2022 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Background and Purpose: To report 9 new cases of non-cavernous sinus dural arteriovenous fistulas (NCS-DAVFs) that closed spontaneously and systematically review reports of other cases in the literature., Material and Methods: We performed a retrospective analysis of 9 cases from 2 institutions of NCS-DAVFs that closed spontaneously. Using PubMed and Scopus in accordance with the PRISMA guidelines, we systematically reviewed English language articles about NCS-DAVFs showing spontaneous closure., Results: Review of the cases from 2 institutions identified 9 cases of NCS-DAVFs showing spontaneous closure in follow-up magnetic resonance angiography (MRA), and the systematic review of the literature yielded an additional 38 cases, which had been diagnosed by repeated arteriography. Collectively, the patients included 23 men and 24 women with a mean age of 54 years. The shunts were located in the transverse-sigmoid sinus in 24 cases (51%), anterior condylar confluence in 11, and other locations in 12. Based on the venous drainage pattern on arteriography, 27 cases (57%) were classified as low-risk NCS-DAVF (without cortical venous reflux) and 17 were classified as high-risk NCS-DAVF (with cortical venous reflux). Shunt closure was observed within 3 months in 17 cases (36%). Extrinsic predisposing factors for shunt closure were detected in 14 cases (30%). These included angiography in 7 cases, sinus recanalization in 4, development of sinus occlusion in 2, and sinus compression by a newly developed hematoma in 1., Conclusion: Spontaneous closures of NCS-DAVFs can occur for both high- and low-risk types. One-third of these closures occur within 3 months., (Copyright © 2020. Published by Elsevier Masson SAS.)

Objective: We investigated the fluoroscopy time (FT) and radiation dose by the number of cerebral angiography (CA) operator experiences to clarify the learning curve of CA., Methods: The subjects were cases for whom CA was performed at our hospital for 5 years between April 2015 and March 2020. Based on the number of CA operator experiences, they were classified into four groups: 1-50 cases (group A), 51-100 cases (group B), 101-200 cases (group C), and 201 cases and later (group D). The FT and radiation dose were retrospectively investigated., Results: Of the 865 consecutive CA cases, 293 cases for follow-up, i.e. after treatment, 54 for arteriovenous shunt diseases, 21 lacking data, and 1 case requiring intervention for thrombosis during CA were excluded. In total, 496 CA cases were investigated. There were 61 cases in group A, 56 cases in group B, 44 cases in group C, and 335 cases in group D, and there was no significant difference in patient background factors among the groups. The median FT and radiation dose (interquartile range) in each group were 20.2 min (14.6) and 374 mGy (185.3) in group A, 14.8 min (12.1) and 366 mGy (167.9) in group B, 10.8 min (6) and 320 mGy (151.7) in group C, and 9.4 min (6.4) and 336 mGy (171) in group D. The FT was significantly shorter in group C than in group A, and significantly shorter in group D than in groups A, B, and C. The radiation dose was significantly lower in groups C and D than in groups A and B., Conclusion: This study suggested that CA can be performed alone after experiencing approximately 100 cases as an operator., Competing Interests: The authors declare no conflicts of interest., (©2022 The Japanese Society for Neuroendovascular Therapy.)

Background: In preoperative embolization for intracranial meningioma, endovascular intratumoral embolization is considered to be more effective for the reduction of tumorous vascularity than proximal feeder occlusion. In this study, we aimed to reveal different efficacies for reducing tumor blood flow in meningiomas by comparing endovascular intratumoral embolization and proximal feeder occlusion using dynamic susceptibility contrast-enhanced perfusion-weighted imaging (DSC-PWI)., Methods: 28 consecutive patients were included. DSC-PWI was performed before and after embolization for intracranial meningiomas. Normalized tumor blood volume (nTBV) of voxels of interest of whole tumors were measured from the DSC-PWI data before and after embolization. ΔnTBV% was compared between the cases that received intratumoral embolization and proximal feeder occlusion., Results: ΔnTBV% in the intratumoral embolization group (42.4±29.8%) was higher than that of the proximal feeder occlusion group (15.3±14.3%, p=0.0039). We used three types of embolic materials and ΔnTBV% did not differ between treatments with or without the use of each material: 42.8±42.4% vs 28.7±20.1% for microspheres (p=0.12), 36.1±20.6% vs 28.1±41.1% for n-butyl cyanoacrylate (p=0.33), and 32.3±37.3% vs 34.1±19.0% for bare platinum coils (p=0.77)., Conclusions: The flow reduction effect of intratumoral embolization was superior to that of proximal feeder occlusion in preoperative embolization for intracranial meningioma in an assessment using DSC-PWI., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To evaluate the efficacy and safety of regenerative treatment for tympanic membrane perforation (TMP) using gelatin sponge, basic fibroblast growth factor (bFGF), and fibrin glue., Methods: This was a multicenter, non-randomized, single-arm study conducted at tertiary referral centers. Twenty patients with chronic TMP (age 23-78 years, 6 males, 14 females) were registered from three institutions. All treated patients were included in the safety analysis population. The edges of the TMP were disrupted mechanically by myringotomy and several pieces of gelatin sponge immersed in bFGF were placed and fixed with fibrin glue to cover the perforation. The TMP was examined 4 ± 1 weeks later. The protocol was repeated up to four times until closure was complete. The main outcome measures were closure or a decrease in size of the TMP, hearing improvement, and air-bone gap evaluated 16 weeks after the final regenerative procedure (FRP). Adverse events (AEs) were monitored throughout the study., Results: Total closure of the TMP at 16 weeks was achieved in 15 out of 20 patients (75.0%, 95% confidence interval [CI]: 50.9%-91.3%) and the mean decrease in size was 92.2% (95%CI: 82.9%-100.0%). The ratio of hearing improvement and the air-bone gap at 16 weeks after FRP were 100% (20/20; 95%CI: 83.2%-100%) and 5.3 ± 4.2 dB (p <0.0001), respectively. Thirteen out of 20 patients (65.0%) experienced at least one AE, but no serious AEs occurred., Conclusion: The results indicate that the current regenerative treatment for TMP using gelatin sponge, bFGF, and fibrin glue is safe and effective., Competing Interests: Declaration of Competing Interest This study was supported by Nobelpharma Co., Ltd., Tokyo, Japan. S. Kanemaru received patent royalties/licensing fees from Nobelpharma Co., Ltd. S.Yamada is a former employee of Nobelpharma Co., Ltd. All the other authors disclose no conflicts of interest., (Copyright © 2021. Published by Elsevier B.V.)

Reactive oxygen species (ROS), a class of highly bioactive molecules, have been widely studied in various types of cancers. ROS are considered to be normal byproducts of numerous cellular processes. Typically, cancer cells exhibit higher basal levels of ROS compared with normal cells as a result of an imbalance between oxidants and antioxidants. ROS have a dual role in cell metabolism: At low to moderate levels, ROS act as signal transducers to activate cell proliferation, migration, invasion, and angiogenesis. In contrast, high levels of ROS cause damage to proteins, nucleic acids, lipids, membranes, and organelles, leading to cell death. Extensive studies have revealed that anticancer therapies that manipulate ROS levels, including immunotherapies, show promising in vitro as well as in vivo results. In this review, we summarize molecular mechanisms and oncogenic functions that modulate ROS levels and are useful for the development of cancer therapeutic strategies. This review also provides insights into the future development of effective agents that regulate the redox system for cancer treatment., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Very few studies have described the blood flow pattern in the ipsilateral ophthalmic artery (OphA) during internal carotid artery (ICA) balloon test occlusion performed to estimate the risk of cerebral ischemia associated with therapeutic ICA sacrifice. This study aimed to investigate the relationship between ipsilateral OphA flow patterns just after ICA temporary occlusion and balloon test occlusion findings. We retrospectively reviewed 32 balloon test occlusion procedures performed at our institution between 2010 and 2019, and analyzed the OphA flow patterns and the conventional balloon test occlusion assessment items: neurological symptoms, stump pressure, stump-pressure ratio, collateral circulations, and venous phase delay. The flow patterns were categorized as type I (retrograde flow reaching the middle cerebral artery [MCA]), type II (retrograde flow to the ICA not reaching the MCA), or type III (no retrograde flow). Tolerance to balloon test occlusion was observed in 4/21 patients (19.0%), 4/6 patients (66.7%), and all five patients with types I, II, and III flows, respectively. The mean pressure ratios during balloon test occlusion in flow types I, II, and III were 35.6% ± 3.5%, 56.4% ± 6.5%, and 69.4% ± 7.1%, respectively (P <0.001). The mean stump pressures in flow types I, II, and III were 36.2 ± 3.6 mmHg, 46.6 ± 6.7 mmHg, and 66.6 ± 7.3 mmHg, respectively (P = 0.003). The mean venous phase delay in flow types I, II, and III were 0.99 ± 0.14 s, 0.25 ± 0.25 s, and 0.0 ± 0.28 s, respectively (P = 0.004). All the above variables showed significant flow-related differences. These results suggest that the OphA flow patterns may provide an additional diagnostic criterion for balloon test occlusion.

Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) has emerged as an ideal target in cancer therapeutics. However, the functions of STEAP1 in liver cancer remain unexplored. The current study aimed to characterize the biological roles of STEAP1 in liver cancer. STEAP1 expression was upregulated in tumor tissues, and high STEAP1 expression was associated with poor clinical outcomes in patients with liver cancer, according to several publicly available datasets. STEAP1 silencing using small interfering RNA inhibited cell proliferation and was accompanied by G 1 arrest induced by the suppression of cyclin D1 and the promotion of p27. STEAP1 silencing suppressed c-Myc expression, which was identified as a component in STEAP1 signal transduction by mining publicly available datasets and was then confirmed by PCR array. In conclusion, the knockdown of STEAP1 in liver cancer cell lines led to inhibition of cell proliferation involving G 1 arrest by suppressing c-Myc. The present study provides a preclinical concept for STEAP1 as a druggable target in liver cancer., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Iijima et al.)

Early reperfusion after endovascular thrombectomy is associated with an improved outcome in ischemic stroke patients; however, the time dependency in elderly patients remains unclear. We investigated the time-outcome relationships in different age subgroups. Of 2420 patients enrolled in the RESCUE-Japan Registry 2 study, a study based on a prospective registry of stroke patients with acute cerebral large-vessel occlusion at 46 centers, we analyzed the data of 1010 patients with successful reperfusion after endovascular therapy (mTICI of 2b or 3). In 3 age subgroups (< 70, 70 to < 80, and ≥ 80 years), the mRS scores at 90 days were analyzed according to 4 categories of onset-to-reperfusion time (< 180, 180 to < 240, 240 to < 300, and ≥ 300 min). In each age subgroup, the distributions of mRS scores were better with shorter onset-to-reperfusion times. The adjusted common odds ratios for better outcomes per 1-category delay in onset-to-reperfusion time were 0.66 (95% CI 0.55-0.80) in ages < 70 years, 0.66 (95% CI 0.56-0.79) in ages 70 to < 80 years, and 0.83 (95% CI 0.70-0.98) in ages ≥ 80 years. Early reperfusion was associated with better outcomes across all age subgroups. Achieving early successful reperfusion is important even in elderly patients.

Traumatic cardiac rupture is mostly accompanied by tamponade and/or hemopericardium. We experienced a rare case of traumatic right atrial rupture with left hemothorax, but without hemopericardium. A 36-year-old male had a traffic accident, and was transported to our hospital. He was in a state of shock caused by massive hemothorax. He underwent emergency operation through median sternotomy. No blood was seen in the pericardium nor injury of any major vessels or lungs. When the heart was exposed, massive bleeding occurred. A tear of 30 mm in length was found in the right atrium at the junction of the superior vena cava. The tear was repaired under cardiopulumonary bypass. Even after surgery, however, he remained unconscious.

Purpose: To elucidate the effect of deep learning-based computer-assisted detection (CAD) on the performance of different-level physicians in detecting intracranial haemorrhage using CT., Methods: A total of 40 head CT datasets (normal, 16; haemorrhagic, 24) were evaluated by 15 physicians (5 board-certificated radiologists, 5 radiology residents, and 5 medical interns). The physicians attended 2 reading sessions without and with CAD. All physicians annotated the haemorrhagic regions with a degree of confidence, and the reading time was recorded in each case. Our CAD system was developed using 433 patients' head CT images (normal, 203; haemorrhagic, 230), and haemorrhage rates were displayed as corresponding probability heat maps using U-Net and a machine learning-based false-positive removal method. Sensitivity, specificity, accuracy, and figure of merit (FOM) were calculated based on the annotations and confidence levels., Results: In patient-based evaluation, the mean accuracy of all physicians significantly increased from 83.7 to 89.7% (p < 0.001) after using CAD. Additionally, accuracies of board-certificated radiologists, radiology residents, and interns were 92.5, 82.5, and 76.0% without CAD and 97.5, 90.5, and 81.0% with CAD, respectively. The mean FOM of all physicians increased from 0.78 to 0.82 (p = 0.004) after using CAD. The reading time was significantly lower when CAD (43 s) was used than when it was not (68 s, p < 0.001) for all physicians., Conclusion: The CAD system developed using deep learning significantly improved the diagnostic performance and reduced the reading time among all physicians in detecting intracranial haemorrhage.

Quantum chemistry studies of biradical systems are challenging due to the required multiconfigurational nature of the wavefunction. In this work, Variational Quantum Eigensolver (VQE) is used to compute the energy profile for the lithium superoxide dimer rearrangement, involving biradical species, on quantum simulators and devices. Considering that current quantum devices can only handle limited number of qubits, we present guidelines for selecting an appropriate active space to perform computations on chemical systems that require many qubits. We show that with VQE performed with a quantum simulator reproduces results obtained with full-configuration interaction (Full CI) for the chosen active space. However, results deviate from exact values by about 39 mHa for calculations on a quantum device. This deviation can be improved to about 4 mHa using the readout mitigation approach and can be further improved to 2 mHa, approaching chemical accuracy, using the state tomography technique to purify the calculated quantum state.

Objective: To determine whether chronic motor deficits secondary to traumatic brain injury (TBI) can be improved by implantation of allogeneic modified bone marrow-derived mesenchymal stromal/stem cells (SB623)., Methods: This 6-month interim analysis of the 1-year double-blind, randomized, surgical sham-controlled, phase 2 Stem Cell Therapy for Traumatic Brain Injury (STEMTRA) trial (NCT02416492) evaluated safety and efficacy of the stereotactic intracranial implantation of SB623 in patients with stable chronic motor deficits secondary to TBI. Patients in this multicenter trial (n = 63) underwent randomization in a 1:1:1:1 ratio to 2.5 × 10 6 , 5.0 × 10 6 , or 10 × 10 6 SB623 cells or control. Safety was assessed in patients who underwent surgery (n = 61), and efficacy was assessed in the modified intent-to-treat population of randomized patients who underwent surgery (n = 61; SB623 = 46, control = 15)., Results: The primary efficacy endpoint of significant improvement from baseline of Fugl-Meyer Motor Scale score at 6 months for SB623-treated patients was achieved. SB623-treated patients improved by (least square [LS] mean) 8.3 (standard error 1.4) vs 2.3 (standard error 2.5) for control at 6 months, the LS mean difference was 6.0 (95% confidence interval 0.3-11.8, p = 0.040). Secondary efficacy endpoints improved from baseline but were not statistically significant vs control at 6 months. There were no dose-limiting toxicities or deaths, and 100% of SB623-treated patients experienced treatment-emergent adverse events vs 93.3% of control patients ( p = 0.25)., Conclusions: SB623 cell implantation appeared to be safe and well tolerated, and patients implanted with SB623 experienced significant improvement from baseline motor status at 6 months compared to controls., Clinicaltrialsgov Identifier: NCT02416492., Classification of Evidence: This study provides Class I evidence that implantation of SB623 was well tolerated and associated with improvement in motor status., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

With the availability of blue light-emitting diode phototherapy devices capable of delivering high-intensity irradiance, neonatologists in Japan are requesting revisions of the 1992 Kobe University treatment criteria for hyperbilirubinemia using total serum/plasma bilirubin (TB) and serum unbound bilirubin (UB) threshold values, especially for indications for exchange transfusion (ET). Retrospective data analysis of 1,184 infants born between January 2012 and November 2014 when the 1992 criteria were followed, we applied revised criteria proposed in 2017 to these infants to assess consequent changes in treatment recommendations. We found that the estimated number of infants with ET indications decreases from 48 to 20, with intensive phototherapy recommended for the remaining 28. Also, the estimated number of infants with phototherapy indications decreases from 446 to 195. We conclude that use of the revised criteria will lead to judicious use and reduction of phototherapy and ET in infants with hyperbilirubinemia., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A 72-year-old man was diagnosed with tumors outside of the stomach and mesentery of the small intestine on abdominal computed tomography. Histopathological examination of an endoscopic ultrasound-guided fine-needle aspiration biopsy specimen confirmed the diagnosis of lymph node metastasis of a neuroendocrine tumor (NET). Gastroscopy, colonoscopy, small bowel capsule endoscopy, somatostatin receptor scintigraphy, and 18F-fluorodeoxyglucose positron emission tomography were performed. However, the primary lesion could not be diagnosed. The patient underwent surgery, and an ileal submucosal tumor, which was not identified preoperatively in addition to the aforementioned abdominal tumors, was detected. All tumors were diagnosed as NET, and the ileal tumor was considered the primary lesion. The patient has shown no recurrence postoperatively. The current study presents a case of an ileal NET with lymph node metastases in a patient in whom the primary lesion remained preoperatively undiagnosed.