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A man in his 80s presented with left hemiparesis and was found to have right internal carotid artery occlusion, and mechanical thrombectomy was successfully performed. An implantable loop recorder implanted 3 years ago showed no episodes of atrial fibrillation (AF) prior to admission. A paroxysmal episode of AF was detected during hospitalisation but did not recur during the following 6 months. Extensive diagnostic evaluation revealed no alternative sources of embolism. One year later, the patient died of septic shock. Autopsy revealed extensive fibrosis of the left atrium and patchy subendocardial transthyretin-type amyloid deposits, consistent with atrial cardiomyopathy. This case demonstrates that even mild or subclinical structural cardiac abnormalities not meeting the diagnostic threshold for overt cardiac disease may contribute to embolic stroke. More broadly, this study provides important clinical evidence supporting the concept of atrial cardiomyopathy as an independent stroke mechanism in the absence of AF.

Esophageal sarcoma is an extremely rare tumor, and a recommended treatment strategy remains unestablished. The present report describes, to the best of our knowledge, the first reported case of unresectable esophageal sarcoma treated with chemoradiotherapy (CRT) followed by salvage robot-assisted minimally invasive esophagectomy (RAMIE). An 82-year-old man presented with dysphagia for solid foods. An esophagogastroduodenoscopy revealed an elevated tumor in the middle thoracic esophagus at a distance of 30-35 cm from the incisors, with preserved endoscopic passage and no additional lesions in the stomach or duodenum. A biopsy demonstrated sarcoma. Enhanced computed tomography showed a middle thoracic esophageal mass, with bulky mediastinal lymph nodes (nos. 101R and 106recR) invading the trachea. No distant metastases were detected, and tumor marker levels remained within normal limits. The patient was diagnosed with esophageal sarcoma with mediastinal lymph node metastases. As the metastatic nodes demonstrated airway invasion, definitive CRT (dCRT) was selected. The regimen consisted of radiotherapy (50.4 Gy in 28 fractions) and fluorouracil plus cisplatin. Following dCRT, the tumor and lymph nodes decreased in size, and a partial response was achieved, making the tumor resectable. Salvage RAMIE with two-field lymphadenectomy, including cervical lymph node dissection of stations 101R and 101L and upper mediastinal dissection, including station 106recR, was subsequently performed, followed by gastric tube reconstruction via the posterior mediastinal route. Pathological examination of the resected specimen revealed no residual tumor. Although a therapeutic effect was observed, a limitation remains in that a definitive diagnosis could not be fully established. A total of 14 months have passed since the initiation of treatment, with no evidence of recurrence. In conclusion, this patient with unresectable locally advanced esophageal sarcoma achieved a complete pathological response after multidisciplinary treatment, with no recurrence observed during the short-term follow-up period.

This case highlights that gastric CIC‐DUX4 rearranged sarcoma is highly aggressive and diagnostically challenging. Early comprehensive genomic profiling was essential for confirming this rare subtype. Despite transient responses to Ewing sarcoma regimens, rapid chemoresistance was observed, emphasizing the need for precise molecular diagnosis and novel therapeutic approaches.

Background Capicua transcriptional repressor-double homeobox 4 sarcoma (CDS) is a rare and aggressive malignant soft tissue tumor that typically arises within the soft tissues. We report an exceptionally rare case of a gastric CDS successfully resected despite its extensive invasion into surrounding organs. Case presentation A 48-year-old male presented with a progressively enlarging abdominal mass. Upper gastrointestinal endoscopy revealed a large ulcerative tumor on the posterior gastric wall. Biopsy results initially suggested a neuroendocrine cell carcinoma. Contrast-enhanced computed tomography showed a 20 cm tumor protruding from the posterior stomach wall, directly invading the pancreas and colon. We performed a multivisceral resection (stomach, pancreatic tail, spleen, and transverse colon) achieving an R0 resection. Pathological examination of the permanent specimen revealed small round cells with high nuclear-to-cytoplasmic ratios. Immunohistochemical staining confirmed the diagnosis of CDS. The patient recovered well and was discharged on postoperative day 33. Conclusions This case report describes the first detailed account of a surgically resected aggressive CDS originating from the stomach.

Background Although many human papillomavirus (HPV)–targeted therapeutic vaccines have been examined for efficacy in clinical trials, none have been translated into clinical use. These previous agents were mostly administered by intramuscular or subcutaneous injection to induce systemic immunity. We investigated the safety and therapeutic efficacy of an HPV-16 E7-expressing lacticaseibacillus-based oral vaccine. Methods In a double-blind, placebo-controlled, randomized trial, a total of 165 patients with HPV-16–positive high-grade cervical intraepithelial neoplasia 2 and 3 were assigned to orally administered placebo or low, intermediate, or high doses of IGMKK16E7 (lacticaseibacillus paracasei expressing cell surface, full-length HPV-16 E7). In the 4 groups, IGMKK16E7 or placebo was administered orally at weeks 1, 2, 4, and 8 postenrollment. The primary outcomes included histopathological regression and IGMKK16E7 safety. Results In per-protocol analyses, histopathological regression to normal (complete response) occurred in 13 (31.7%) of 41 high-dose recipients and in 5 (12.5%) of 40 placebo recipients (rate difference = 19.2, 95% confidence interval [CI] = 0.5 to 37.8). In patients positive for HPV-16 only, the clinical response rate was 40.0% (12 of 30) in high-dose recipients and 11.5% (3 of 26) in recipients of placebo (rate difference = 28.5, 95% CI = 4.3 to 50.0). There was no difference in adverse events that occurred in the high-dose and placebo groups (P = .83). The number of HPV-16 E7–specific interferon-γ producing cells within peripheral blood increased with level of response (stable disease, partial, and complete responses; P = .004). The regression to normal (complete response) rates among recipients with high levels of immune response were increased in a dose-dependent manner. Conclusion This trial demonstrates safety of IGMKK16E7 and its efficacy against HPV-16–positive cervical intraepithelial neoplasia 2 and 3. IGMKK16E7 is the first oral immunotherapeutic vaccine to show antineoplastic effects. Trial registration jRCT2031190034.

TAL1 plays pivotal roles in vascular and hematopoietic developments through the complex with LMO2 and GATA1. Hemangioblasts, which have a differentiation potential for both endothelial and hematopoietic lineages, arise in the primitive streak and migrate into the yolk sac to form blood islands, where primitive hematopoiesis occurs. ZFAT (a zinc-finger gene in autoimmune thyroid disease susceptibility region / an immune-related transcriptional regulator containing 18 C₂H₂-type zinc-finger domains and one AT-hook) was originally identified as an immune-related transcriptional regulator containing 18 C₂H₂-type zinc-finger domains and one AT-hook, and is highly conserved among species. ZFAT is thought to be a critical transcription factor involved in immune-regulation and apoptosis; however, developmental roles for ZFAT remain unknown. Here we show that Zfat-deficient (Zfat⁻ / ⁻) mice are embryonic-lethal, with impaired differentiation of hematopoietic progenitor cells in blood islands, where ZFAT is exactly expressed. Expression levels of Tal1, Lmo2, and Gata1 in Zfat⁻ / ⁻ yolk sacs are much reduced compared with those of wild-type mice, and ChIP-PCR analysis revealed that ZFAT binds promoter regions for these genes in vivo. Furthermore, profound reduction in TAL1, LMO2, and GATA1 protein expressions are observed in Zfat⁻ / ⁻ blood islands. Taken together, these results suggest that ZFAT is indispensable for mouse embryonic development and functions as a critical transcription factor for primitive hematopoiesis through direct-regulation of Tal1, Lmo2, and Gata1. Elucidation of ZFAT functions in hematopoiesis might lead to a better understanding of transcriptional networks in differentiation and cellular programs of hematopoietic lineage and provide useful information for applied medicine in stem cell therapy.

Background Although therapeutic human papillomavirus vaccines could offer a noninvasive treatment for patients with cervical intraepithelial neoplasia, none has been clinically implemented. Oral administration of the therapeutic human papillomavirus vaccine IGMKK16E7 results in the histological regression of human papillomavirus 16–positive cervical intraepithelial neoplasia 2/3 to normal (complete response). We investigated biomarkers that could predict complete response after oral administration of IGMKK16E7. Methods Forty-two patients administered high-dose oral IGMKK16E7 in a phase I/II trial were included. Cervix-exfoliated cells were collected before vaccine administration. Gene expression of CD4, CD8, FOXP3, programmed cell death 1 protein, CTLA4, CD103, CD28, CD80, CD86, and programmed cell death 1 ligand 1 in the cells was measured by quantitative reverse transcriptase–polymerase chain reaction. Receiver operating characteristic curve analysis and Mann-Whitney tests were used to explore potential biomarkers. Pearson correlation coefficient analysis was used to correlate gene expression profiles with clinical outcome. Results The only predictive biomarker of vaccine response for which receiver operating characteristic curve analysis showed significant diagnostic performance with histological complete response was CD86 (area under the curve = 0.71, 95% confidence interval = 0.53 to 0.88, P = .020). Patients with complete response had significantly lower CD86 expression (CD86-low) than patients with no complete response (P = .035). The complete response rates for CD86-low and CD86-high patients were 50% and 19%, respectively, and CD86-low patients had a significantly higher complete response rate (P = .047). Compared with all patients, the CD86-low group had a 1.5-fold increase in the complete response rate. Gene expression of CD86 and CTLA4 showed the strongest positive correlation with clinical outcomes in the incomplete response group (P < .001). Conclusion Low expression of CD86 in exfoliated cervical cells can be used as a pretreatment biomarker to predict histological complete response after IGMKK16E7 administration.

Osteoclasts play a crucial role in bone homeostasis by forming resorption pits on bone surfaces, resulting in bone resorption. The osteoclast expression of Rab38 protein is highly induced during differentiation from macrophages. Here we generated mice with double knockout (DKO) of Rab38 and its paralogue, Rab32, to investigate the roles of these proteins in osteoclasts. Bone marrow-derived macrophages from Rab32/38 DKO mice differentiated normally into osteoclasts in vitro. However, DKO osteoclasts showed reduced bone resorption activity. These osteoclasts also demonstrated defective secretion of tartrate-resistant acid phosphatase and cathepsin K into culture medium. Furthermore, the plasma membrane localization of a3, an osteoclast-specific a subunit of V-ATPase, was abrogated in DKO mice, substantiating the reduced resorption activity. In vivo, Rab32- and Rab38-positive cells were attached to the bone surface. Eight-week-old DKO mice showed significantly thickened trabecular bones in micro-CT and histomorphometry analysis, as well as reduced serum levels of cross-linked C-telopeptide of type I collagen, indicating diminished bone resorption in vivo. In DKO male mice over 10 weeks of age, hyperostosis appeared at the talofibular syndesmosis, the distal junction of the tibia and fibula. Furthermore, middle-aged mice (10 to 12 months of age) exhibited kyphosis, which is not usually observed in wild-type male mice until around 24 months of age. These results indicate that Rab32 and Rab38 contribute to osteoclast function by supporting intracellular traffic, thereby maintaining normal bone homeostasis.Key words: Rab32, Rab38, osteoclast, lysosome-related organelle, secretory lysosome

Pain management is a major medical issue. However, current medical education in Japan is inadequate with regard to training students to properly assess patients with acute and chronic pain and plan their treatment. Therefore, starting in 2019, Hyogo Medical University established a multidisciplinary educational system to better train medical students to provide pain care. The course, called clinical pain study, is offered to fourth- and fifth-year medical students. Fourth-year students learn the scientific aspects of pain through clinical practice. In this study, we assessed students’ understanding of pain management based on the results of pretests and posttests performed before and after their practicum. These tests were administered from November 2019 to April 2022 to 263 fourth- and fifth-year medical students who took the clinical pain study class. The test results were compared in terms of the percentage of correct answers and the total score for each question using McNemar’s chi-square test and paired t-tests, respectively. The results showed a significant improvement in the mean of the total score, confirming the improvement in medical students’ knowledge (6.43 vs. 7.35 points; p<0.001). Based on the results, overall, pain education at the university has had positive outcomes and will therefore be continued in the future.

Improvement of leaf photosynthesis is an important strategy for greater crop productivity. Here we show that the quantitative trait locus GPS ( GREEN FOR PHOTOSYNTHESIS ) in rice ( Oryza sativa L.) controls photosynthesis rate by regulating carboxylation efficiency. Map-based cloning revealed that GPS is identical to NAL1 ( NARROW LEAF1 ), a gene previously reported to control lateral leaf growth. The high-photosynthesis allele of GPS was found to be a partial loss-of-function allele of NAL1 . This allele increased mesophyll cell number between vascular bundles, which led to thickened leaves and it pleiotropically enhanced photosynthesis rate without the detrimental side effects observed in previously identified nal1 mutants, such as dwarf plant stature. Furthermore, pedigree analysis suggested that rice breeders have repeatedly selected the high-photosynthesis allele in high-yield breeding programs. The identification and utilization of NAL1 ( GPS ) can enhance future high-yield breeding and provides a new strategy for increasing rice productivity.