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Immunogenic cell death (ICD) enhances immunogenicity and activates antitumor immune responses. ICD induction by anticancer drugs may be effective against microsatellite-stable colorectal cancers (CRCs) that are less responsive to immune checkpoint inhibitors. Calreticulin (CRT) is crucial in ICD, promoting dendritic cell phagocytosis and initiating antitumor immunity. This study investigated CRT exposure mechanisms in four CRC cell lines and three human CRC organoids. Flow cytometry and immunofluorescence showed that oxaliplatin and 5-fluorouracil caused CRT exposure in all models. Despite CRT's association with endoplasmic reticulum stress, Western blot analysis showed no increase in this stress. These findings suggest alternative pathways. RNA sequencing identified enrichment of p53 signaling pathway genes, including TP53I3, TP53INP1, and YPEL3, which were confirmed by RT-qPCR. These results suggest that the p53 signaling pathway plays an important role in CRT exposure induced by anticancer drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The 6th Asia Partnership Conference of Regenerative Medicine (APACRM) was held in person with online on April 20, 2023, to promote the regulatory harmonization of regenerative medicine products throughout Asia. Recognizing domestic regulatory guidelines within each country and region and the underlying rationales are important initial steps toward harmonizing regulations. The 6th APACRM featured an open dialog regarding non-clinical evaluation for advanced CAR-T products, regulation of clinical trials for AAV-based gene therapies, and cell and gene therapies provided to patients as medical care/medical practices without market authorization through presentations from the industry and panel discussions with regulatory agencies. The latest updates on regenerative medicine in each country and region are introduced. This paper summarizes the proceedings of the 6th APACRM for public dissemination to foster future discussions., (© 2024 The Author(s).)

Background: The fibrosis-4 (FIB4) index, a simple, noninvasive marker used for hepatic diseases, represents adverse outcomes. The aim of the present study was to evaluate whether the FIB4 index can predict adverse outcomes in patients with ST-elevation myocardial infarction (STEMI)., Methods: We investigated patients with STEMI who underwent primary percutaneous coronary intervention (PCI) and were alive at discharge. The cut-off FIB4 index at discharge was investigated using the survival classification and regression tree (CART) model to predict adverse outcomes. The primary outcome was all-cause mortality., Results: Between January 2006 and December 2018, 1354 patients with STEMI (median age, 68 years; men, 76.1%) were investigated. The median value of the FIB4 index was 1.21 (0.84-1.78). The CART model divided the study population into low (FIB4 index <0.945; n = 435), intermediate (0.945 ≤ FIB4 index < 2.185; n = 692), and high (FIB4 index ≥2.185; n = 227) groups based on the significant predictive values for all-cause death. During a median follow-up period of 4.3 years, all-cause death occurred in 208 patients (15.4%). The Kaplan-Meier analysis showed a significant increase in mortality with higher FIB4 index values (log-rank, P < 0.001). The multivariate Cox regression model revealed that the FIB4 index was an independent risk predictor for all-cause death in patients with STEMI [low group as reference vs. intermediate group, hazard ratio: 1.975; 95% confidence interval (CI): 1.166-3.346; P = 0.011 and vs. high group, hazard ratio: 4.633; 95% CI: 2.549-8.418; P < 0.001]., Conclusions: The FIB4 index was associated with the risk of all-cause mortality in patients with STEMI who underwent primary PCI., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Epicardial adipose tissue (EAT) is closely associated with atrial fibrillation (AF), suggesting that it may be one of the causes of AF progression. However, it is unclear whether AF affects EAT., Objective: This study aimed to demonstrate that sinus rhythm restoration reduces EAT volume (EATV) through left atrial reverse remodeling (LARR)., Methods: We analyzed data from 247 patients who underwent cryoballoon ablation for AF. EATV was assessed by contrast-enhanced computed tomography with a 3-dimensional analysis workstation, evaluating EATV surrounding the entire heart (Total-EATV) and left atrium (LA-EATV) at baseline and 6 months after cryoballoon ablation., Results: At 6 months, all patients but one with persistent AF were in sinus rhythm. Total-EATV and LA-EATV were both significantly decreased in patients with persistent AF (n = 33; Total-EATV: 148.8 ± 53.3 mL to 142.9 ± 53.5 mL [P = .01]; LA-EATV: 26.8 ± 11.3 mL to 25.2 ± 10.7 mL [P = .01]). No changes were observed in patients with paroxysmal AF (n = 214). Persistent AF was more strongly associated with LARR than paroxysmal AF (odds ratio, 2.34; 95% confidence interval, 1.01-5.44; P = .05). LARR showed an independent correlation with both Total-EATV and LA-EATV reduction (odds ratio, 1.78 [P = .04] and 2.80 [P < .001], respectively)., Conclusion: These findings suggest a novel "AF begets EAT" theory, complementing the previously accepted role of EAT as a cause of AF and supporting the "AF begets AF" mechanism., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Introduction: BRAF mutations in bladder cancer are rare. MEK inhibitors have excellent clinical benefits in the treatment of melanoma., Case Presentation: A 60-year-old male was diagnosed with muscle-invasive bladder cancer and underwent total cystectomy and ileal conduit diversion. Despite 4 cycles of gemcitabine and cisplatin chemotherapy and 3 courses of pembrolizumab, the left obturator lymph node enlarged. Cancer multi-gene panel testing confirmed the BRAF G469A mutation and trametinib was recommended. Three months after the initiation of trametinib (2 mg, qd), the left obturator lymph node shrank by more than 50%. The disease has remained stable for more than 18 months., Conclusion: The present case indicates the potential of trametinib to treat mBUC patients with the BRAF G469A mutation in this setting., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association.)

Background: Evidence regarding the association between hyperuricemia and arrhythmia recurrence after catheter ablation for paroxysmal atrial fibrillation (AF) is scarce. We investigated whether hyperuricemia predicts arrhythmia recurrence after catheter ablation for paroxysmal AF and the relationship between hyperuricemia and alcohol consumption in AF recurrence., Methods: Patients who underwent catheter ablation for paroxysmal AF were divided into the hyperuricemia (index serum uric acid [UA] >7.0 mg/dL; n  = 114) and control (UA ≤7.0 mg/dL; n  = 609) groups and were followed for a median of 24 (12-48) months after ablation., Results: The hyperuricemia group had more patients with an alcohol intake of ≥20 g/day (33.3% vs. 22.7%, p  = .017) and a lower incidence of AF-free survival ( p  = .019). Similarly, those with an alcohol intake of ≥20 g/day had a lower incidence of AF-free survival than other patients. Multivariate Cox regression analysis revealed the following independent predictors of AF recurrence (adjusted hazard ratio, 95% confidence interval): hyperuricemia (1.64, 1.12-2.40), female gender (1.91, 1.36-2.67), brain natriuretic peptide level >100 pg/mL (1.59, 1.14-2.22), and alcohol consumption ≥20 g/day (1.49, 1.03-2.15) (all p  < .05). In addition, causal mediation analysis revealed that alcohol consumption of ≥20 g/day directly affected AF recurrence, independent of hyperuricemia., Conclusions: Patients with hyperuricemia may be at a high risk of arrhythmia recurrence after catheter ablation for paroxysmal AF. Although high alcohol consumption may contribute to increased UA levels, the presence of hyperuricemia may independently predict AF recurrence., Competing Interests: The authors declare that there are no conflicts of interest., (© 2024 The Author(s). Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of Japanese Heart Rhythm Society.)

ABCC3 (also known as MRP3) is an ATP binding cassette transporter for bile acids, whose expression is downregulated in colorectal cancer through the Wnt/β-catenin signaling pathway. However, it remained unclear how downregulation of ABCC3 expression contributes to colorectal carcinogenesis. We explored the role of ABCC3 in the progression of colorectal cancer-in particular, focusing on the regulation of bile acid export. Gene expression analysis of colorectal adenoma isolated from familial adenomatous polyposis patients revealed that genes related to bile acid secretion including ABCC3 were downregulated as early as at the stage of adenoma formation. Knockdown or overexpression of ABCC3 increased or decreased intracellular concentration of deoxycholic acid, a secondary bile acid, respectively, in colorectal cancer cells. Forced expression of ABCC3 suppressed deoxycholic acid-induced activation of MAPK signaling. Finally, we found that nonsteroidal anti-inflammatory drugs increased ABCC3 expression in colorectal cancer cells, suggesting that ABCC3 could be one of the targets for therapeutic intervention of familial adenomatous polyposis. Our data thus suggest that downregulation of ABCC3 expression contributes to colorectal carcinogenesis through the regulation of intracellular accumulation of bile acids and activity of MAPK signaling., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: We developed a novel photoacoustic needle, which emits ultrasound produced by the photoacoustic effect. This study focused on the most common "pitfall" associated with placement during ultrasound-guided vascular access, which is misidentification of the needle tip., Methods: The study was conducted as a prospective cohort study using a questionnaire. The authors intentionally created two successful and one failed ultrasound-guided central venous catheterization videos using the photoacoustic needle on a simulator. Each of these three videos was then split into two movies for viewing, one with standard ultrasound images only and the second including the images from the photoacoustic needle, for a total of six movies., Results: Participants who were 18 anesthesiologists, 12 residents, and 10 medical students, watched each of the six movies and completed a survey whether the puncture was successful or not. In the results, there was a significant difference in the percentage of correct answers whether the movie depicted successful or failed puncture with and without the photoacoustic ultrasound ( p  = 0.0001)., Conclusion: The novel photoacoustic needle improved the ability to identify the needle tip on recorded videos. It may have efficacy to prevent serious mechanical complication during the ultrasound-guided vascular access in clinical practice., Competing Interests: DisclosureThis work was performed in Kyorin University School of Medicine, 6-20-2 Shinkawa, Miaka, Tokyo 181-8611, Japan. Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: K. Y. (the fourth coauthor) and H.K. (the fifth coauthor) are employees of the FUJIFILM Co. J.T. (the second coauthor) is a technical adviser of the Nippon Covidien Co. (Japan) and has done an ultrasound-guided technical training course held by the company.

Background and Purpose: Colorectal cancer progression from adenoma to cancer is a time-intensive process; however, the interaction between normal fibroblasts (NFs) with early colorectal tumors, such as adenomas, remains unclear. Here, we analyzed the response of the microenvironment during early tumorigenesis using co-cultures of organoids and NFs., Materials and Methods: Colon normal epithelium, adenoma, cancer organoid, and NFs were established and co-cultured using Transwell inserts. Microarray analysis of NFs was performed to identify factors expressed early in tumor growth. Immunostaining of clinical specimens was performed to localize the identified factor. Functional analysis was performed using HCT116 cells. Serum DKK1 levels were measured in patients with colorectal cancer and adenoma., Results: Colorectal organoid-NF co-culture resulted in increased organoid diameter and cell viability in normal epithelial and adenomatous organoids but not in cancer organoids. Microarray analysis of NFs revealed 18 genes with increased expression when co-cultured with adenoma and cancer organoids. Immunohistochemical staining revealed DKK1 expression in the tumor stroma from early tumor growth. DKK1 stimulation reduced HCT116 cell proliferation, while DKK1 silencing by siRNA transfection increased cell proliferation. Serum DKK1 level was significantly higher in patients with advanced cancer and adenoma than in controls. Serum DKK1 level revealed area-under-the-curve values of 0.78 and 0.64 for cancer and adenoma, respectively., Conclusion: These findings contribute valuable insights into the early stages of colorectal tumorigenesis and suggest DKK1 as a tumor suppressor. Additionally, serum DKK1 levels could serve as a biomarker to identify both cancer and adenoma, offering diagnostic possibilities for early-stage colon tumors. The present study has a few limitations. We considered using DKK1 as a candidate gene for gene transfer to organoids and NFs; however, it was difficult due to technical problems and the slow growth rate of NFs. Therefore, we used cancer cell lines instead. In addition, immunostaining and ELISA were based on the short-term collection at a single institution, and further accumulation of such data is desirable. As described above, most previous reports were related to advanced cancers, but in this study, new findings were obtained by conducting experiments on endoscopically curable early-stage tumors, such as adenomas., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Competing Interests: Conflicts of Interest: The authors declare that there are no relevant conflicts of interest.

The 5th Asia Partnership Conference of Regenerative Medicine (APACRM) was held online on April 7, 2022 to promote regulatory harmonization of regenerative medicine products throughout Asia. The recognition of domestic regulatory guidelines within each country and region and the underpinning rationales are important initial steps toward the harmonization of regulations. The 5th APACRM featured open dialog regarding non-clinical, quality and environmental impact assessment settings for cell and gene therapy products through presentations from the industry and panel discussions with regulatory agencies. The latest updates on regenerative medicine fields in each country and region were also introduced. This paper summarizes the proceedings of the 5th APACRM for public dissemination to foster future discussion., Competing Interests: Declaration of Competing Interest The views and opinions expressed in this article represent the personal ideas of the participants and are not necessarily the official positions of the agency. All authors, except for BHC are employees of companies developing cellular therapies, providing testing or enabling technologies for the manufacturing of cellular therapies., (Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Clinical outcomes concerning the efficacy of excimer laser coronary angioplasty (ELCA) in real-world cases of acute myocardial infarction (MI) are limited. We evaluated and compared the impact of ELCA with manual aspiration thrombectomy on myocardial salvage and left ventricular (LV) systolic/diastolic function in patients with ST-segment elevation MI (STEMI) using nuclear scintigraphy.  We enrolled 143 consecutive patients with STEMI treated with ELCA (63 patients) or manual aspiration thrombectomy (80 patients) between September 2016 and December 2020 in a single-center hospital. We evaluated the peak creatine kinase (CK)/ creatine kinase-myocardial band (CK-MB) levels and performed single-photon emission computed tomography (SPECT) analyses with Quantitative Gated SPECT and Quantitative Perfusion SPECT (Auto QUANT 7.2) at 3-10 days using 123 I-BMIPP and 3 months following percutaneous coronary intervention using 99m Tc-tetrofosmin to evaluate myocardial salvage and LV systolic/diastolic function. No significant difference was observed in the patient and periprocedural characteristics. Peak CK-MB level was significantly different between the groups (ELCA group, 190.0 [70.5-342.0] IU/L vs. aspiration group, 256.5 [157.0-354.8] IU/L, p = 0.047). Although no significant difference was observed in myocardial salvage, significant improvement in the LV ejection fraction (14.1 [6.2-19.8]% vs. 9.5 [3.9-15.3]%, respectively, p = 0.018) and peak emptying rate (-0.54 [-1.02- (-0.27)] mL/s vs. -0.38 [-0.76- (-0.05)] mL/s, respectively, p = 0.017) were detected. ELCA could suppress the myocardial deviation enzymes and potentially improve systolic function compared to manual aspiration thrombectomy in patients with STEMI., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

We report a case of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) after total proctocolectomy followed with ileal pouch-anal anastomosis (TPC-IPAA) for ulcerative colitis (UC). The patient was a 46-year-old woman. She was diagnosed with UC of pancolitis in 2000. High grade dysplasia was detected in the transverse colon after a surveillance colonoscopy in 2021. She underwent laparoscopy-assisted TPC-IPAA. On the sixth postoperative day, she had a decreased level of consciousness that worsened on the following day. Her laboratory data showed a serum sodium level of 108 mEq/L and the plasma osmolality was 234 mOsm/kg. We did not find any other abnormalities in the laboratory examination that could cause hyponatremia. Computed tomography scan showed no central nervous system disturbances such as a pituitary tumor, antidiuretic hormone-producing tumors, or pulmonary diseases. The patient was diagnosed with Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) caused by surgical invasion. We started to administer 3% sodium chloride slowly to improve the hyponatremia. Her serum sodium level became normal and stable. Although it is rare for SIADH to be caused by abdominal surgery, if hyponatremia is observed after surgery, the possibility of postoperative SIADH should be considered., (© 2022. Japanese Society of Gastroenterology.)

The patient was referred to our hospital because of bloody stool and anorectal pain, and a colonoscopy revealed a tumor in the lower rectum. Although no distant metastasis was found, the tumor was suspected to have invaded the distal prostate. Neoadjuvant chemoradiotherapy(45 Gy/25 Fr with S-1)resulted in tumor shrinkage and symptomatic improvement, however, the primary tumor remained in close proximity to the prostate and urethra. Thus, we performed a robot-assisted abdominoperineal resection and Retzius-sparing prostatectomy in collaboration with the urology department. The surgical margins were negative and radical resection was achieved. Although minor vesicourethral anastomotic leakage was observed, it recovered conservatively. The patient has been alive 1 year postoperatively without recurrence. The patient initially had urinary incontinence, but it gradually improved. Although a total pelvic resection could have been considered, the robot-assisted surgery made it possible to preserve the urinary tract. The future application of robot-assisted surgery in extended surgery is expected.

A 56-year-old man was referred to our hospital with an awareness of anal tumor. The tumor extended from the anal verge to the back of left testicle. Colonoscopy showed no tumor in the rectum and the anal canal. Biopsy showed mucus- producing adenocarcinoma(sig), and we diagnosed anal canal adenocarcinoma with immunostaining. Laparoscopic abdominoperineal rectal resection and perineal reconstruction with the V-Y fasciocutaneous flap closure technique. The patient had no major postoperative complications, and was discharged on 23rd postoperative day. Pathological examination revealed that the tumor was pT3N0M0, pStage ⅡB. The patient received adjuvant chemotherapy with CAPOX and has survived 12 months without recurrence. Immunostaining may be used to diagnose the signet-ring cell carcinoma without tumor of anal canal. In addition, reconstruction of the perineum for large anal tumors is useful.

Both viable and non-viable orally administered Lacticaseibacillus rhamnosus CRL1505 modulate immunity in local (intestine) and distal (respiratory) mucosal sites. So, intestinal adhesion and colonization are not necessary for this probiotic strain to exert its immunomodulatory effects. In this work, a mucus-binding factor knockout CRL1505 strain (Δ mbf CRL1505) was obtained and the lack of binding ability to both intestinal epithelial cells and mucin was demonstrated in vitro. In addition, two sets of in vivo experiments in 6-week-old Balb/c mice were performed to evaluate Δ mbf CRL1505 immunomodulatory activities. (A) Orally administered Δ mbf CRL1505 prior to intraperitoneal injection of the Toll-like receptor 3 (TLR3) agonist poly(I:C) significantly reduced intraepithelial lymphocytes (CD3 + NK1.1 + CD8αα + ) and pro-inflammatory mediators (TNF-α, IL-6 and IL-15) in the intestinal mucosa. (B) Orally administered Δ mbf CRL1505 prior to nasal stimulation with poly(I:C) significantly decreased the levels of the biochemical markers of lung tissue damage. In addition, reduced recruitment of neutrophils and levels of pro-inflammatory mediators (TNF-α, IL-6 and IL-8) as well as increased IFN-β and IFN-γ in the respiratory mucosa were observed in Δ mbf CRL1505-treated mice when compared to untreated control mice. The immunological changes induced by the Δ mbf CRL1505 strain were not different from those observed for the wild-type CRL1505 strain. Although it is generally accepted that the expression of adhesion factors is necessary for immunobiotics to induce their beneficial effects, it was demonstrated here that the mbf protein is not required for L. rhamnosus CRL1505 to exert its immunomodulatory activities in local and distal mucosal sites. These results are a step forward towards understanding the mechanisms involved in the immunomodulatory capabilities of L. rhamnosus CRL1505.

The 4th Asia Partnership Conference of Regenerative Medicine (APACRM) was held online on April 15, 2021, to promote regulatory harmonization of regenerative medicine products throughout Asia. Recognizing domestic regulatory guidelines within each country and region, and their underpinning rationales, is an important initial step toward a convergence of regulations. The 4th APACRM consisted of an open dialog with regulatory agencies regarding nonclinical and quality settings for cell therapy products (CTPs) through industry presentations and panel discussions with regulatory agencies. The latest updates on regenerative medicine fields in each country and region, and specific regulatory schematics in Japan, were also introduced. The objective of this paper is to summarize the proceedings of the 4th APACRM for public dissemination and to foster further discussion in the future., (Copyright © 2022 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

A 56-year-old man was referred to our hospital for multidisciplinary treatment of advanced sigmoid colon carcinoma with a suspected bladder invasion. The patient received 8 courses of modified Leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6)plus panitumumab as neoadjuvant chemotherapy for reliable and safe radical resection after ileostomy construction. There was a significant reduction in the tumor size following chemotherapy; hence, low anterior resection was performed. In addition, since preoperative and intraoperative findings suggested bladder invasion, a total cystectomy with ileal conduit urinary diversion was performed. The pathological diagnosis was ypT4b, N0, M0, and ypStage Ⅱc, with all surgical margins being negative. Subsequently, the patient received adjuvant chemotherapy with 4 courses of mFOLFOX6, and his condition improved with no incidence of cancer recurrence following 8 months after the operation. Neoadjuvant chemotherapy for locally advanced colon cancer is one of the effective treatments for reliable and safe radical resection.

A 70's woman complaining blood stool and lower abdominal pain visited a local doctor and was given the diagnosis of rectal cancer by colonoscopy. CT, MRI, and bone scintigraphy revealed multiple lymph node and bone metastasis and peritoneal dissemination. She had developed disseminated intravascular coagulation(DIC)during hospitalization, and the cause was considered to be disseminated carcinomatosis of the bone marrow. Thus, we emergently started chemotherapy with mFOLFOX6, in conjunction with anticoagulation therapy, and the DIC was resolved 11 days after the introduction. Partial response was achieved and the chemotherapy has been continued after 5 months from the onset of the DIC. Since the prognosis of solid tumor patients who developed DIC has been reported to be extremely poor, prompt introduction of chemotherapy should be considered.

The ATP-binding cassette subfamily G member 2 (ABCG2) transporter is involved in the development of multidrug resistance in cancer patients. Many inhibitors of ABCG2 have been reported to enhance the chemosensitivity of cancer cells. However, none of these inhibitors are being used clinically. The aim of this study was to identify novel ABCG2 inhibitors by high-throughput screening of a chemical library. Among the 5812 compounds in the library, 23 compounds were selected in the first screening, using a fluorescent plate reader-based pheophorbide a (PhA) efflux assay. Thereafter, to validate these compounds, a flow cytometry-based PhA efflux assay was performed and 16 compounds were identified as potential inhibitors. A cytotoxic assay was then performed to assess the effect these 16 compounds had on ABCG2-mediated chemosensitivity. We found that the phenylfurocoumarin derivative (R)-9-(3,4-dimethoxyphenyl)-4-((3,3-dimethyloxiran-2-yl)methoxy)-7H-furo [3,2-g]chromen-7-one (PFC) significantly decreased the IC 50 of SN-38 in HCT-116/BCRP colon cancer cells. In addition, PFC stimulated ABCG2-mediated ATP hydrolysis, suggesting that this compound interacts with the substrate-binding site of ABCG2. Furthermore, PFC reversed the resistance to irinotecan without causing toxicity in the ABCG2-overexpressing HCT-116/BCRP cell xenograft mouse model. In conclusion, PFC is a novel inhibitor of ABCG2 and has promise as a therapeutic to overcome ABCG2-mediated MDR, to improve the efficiency of cancer chemotherapy.

The splicing of microexons (very small exons) is frequently dysregulated in the brain of individuals with autism spectrum disorder. However, little is known of the patterns, regulatory mechanisms and roles of microexon splicing in cancer. We here examined the transcriptome-wide profile of microexon splicing in matched colorectal cancer (CRC) and normal tissue specimens. Out of 1492 microexons comprising 3 to 15 nucleotides, 21 (1%) manifested differential splicing between CRC and normal tissue. The 21 genes harboring the differentially spliced microexons were enriched in gene ontology terms related to cell adhesion and migration. RNA interference-mediated knockdown experiments identified two splicing factors, RBFOX2 and PTBP1, as regulators of microexon splicing in CRC cells. RBFOX2 and PTBP1 were found to directly bind to microexon-containing pre-mRNAs and to control their splicing in such cells. Differential microexon splicing was shown to be due, at least in part, to altered expression of RBFOX2 and PTBP1 in CRC tissue compared to matched normal tissue. Finally, we found that changes in the pattern of microexon splicing were associated with CRC metastasis. Our data thus suggest that altered expression of RBFOX2 and PTBP1 might influence CRC metastasis through the regulation of microexon splicing., (© 2021 UICC.)

Background Aims: Cell-based regenerative medicine is an innovative field that can potentially alter the overall survival and quality of life of patients with devastating diseases. Several cell therapy products (CTPs) have been approved within the last two decades, and more are under development. The establishment of an effective developmental strategy in accordance with the regulatory bodies of each country/region is crucial for fast delivery of each respective CTP. In particular, facilitating investigational new drug (IND) approval is important for accelerating the transition from non-clinical to clinical research/trial phases., Methods: Here the authors compared the non-clinical prerequisites for initiating clinical studies in five Asian countries/regions (India, China, Korea, Taiwan and Japan) from an industry viewpoint. The authors first identified the differences and tried to clarify the perspectives/considerations underpinning the different requirements., Results: The authors' findings revealed that differences in regulations and development experiences, especially with CTPs, have led to clear differences in the non-clinical study package and its corresponding study design., Conclusions: By sharing experiences of the research and development of CTPs among Asian countries/regions and including not only industry but also regulatory authorities, we will be able to expedite cross-border IND approval and eventually contribute to the early delivery of innovative CTPs to many Asian patients., (Copyright © 2021 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment and have been shown to promote cancer aggressiveness. In our previous study, analysis of expression profiles obtained from paired CAFs and normal fibroblasts from colorectal cancer (CRC) tissue revealed that gene sets related to the Wnt signaling pathway were highly enriched in colorectal CAFs. Furthermore, among the components of the β-catenin-independent Wnt pathway, Wnt5a was highly expressed in CAFs. Since Wnt5a is considered to be a regulator of CRC progression in CAFs, we performed immunohistochemical analysis on Wnt5a in 171 patients who underwent surgery for CRC. Positive staining for Wnt5a was often found in cancer stroma, particularly in fibromatous areas, although the immunoreactivity for Wnt5a was weak in cancer cells. Wnt5a status in CAFs was significantly associated with tumor size, depth of invasion, lymphatic and vascular invasion, lymph node metastasis, TNM stage, and recurrence. Subsequent in vitro analyses using human recombinant Wnt5a protein revealed that cancer cell proliferation and migration were significantly increased by stimulation with Wnt5a. Our findings suggest that Wnt5a-derived CAFs play a crucial role in CRC progression and have potential as a target of anti-cancer therapies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Reduced glucose uptake into the skeletal muscle is an important pathophysiological abnormality in type 2 diabetes, and is caused by impaired translocation of glucose transporter 4 (GLUT4) to the skeletal muscle cell surface. Here, we show a xanthene derivative, DS20060511, induces GLUT4 translocation to the skeletal muscle cell surface, thereby stimulating glucose uptake into the tissue. DS20060511 induced GLUT4 translocation and stimulated glucose uptake into differentiated L6-myotubes and into the skeletal muscles in mice. These effects were completely abolished in GLUT4 knockout mice. Induction of GLUT4 translocation by DS20060511 was independent of the insulin signaling pathways including IRS1-Akt-AS160 phosphorylation and IRS1-Rac1-actin polymerization, eNOS pathway, and AMPK pathway. Acute and chronic DS20060511 treatment attenuated the glucose intolerance in obese diabetic mice. Taken together, DS20060511 acts as a skeletal muscle-specific GLUT4 translocation enhancer to facilitate glucose uptake. Further studies of DS20060511 may pave the way for the development of novel antidiabetic medicines., (© 2021. The Author(s).)

Background: Pancreatic serous cystic neoplasm (SCN) is an uncommon exocrine neoplasm, which is believed to be a benign entity. However, some of these neoplasms may occasionally attain metastatic ability. Von Hippel-Lindau disease (VHL) manifests a dominantly inherited systemic syndrome accompanied by several benign or malignant tumors, including cystic tumors, in various organs. We describe here a long-term survival case who underwent surgical resection for metachronous liver metastases of pancreatic SCN associated with VHL disease., Case Presentation: A 35-year-old woman with VHL underwent total pancreatectomy and right nephrectomy for pancreatic SCN and renal cell carcinoma, respectively. At the 4th year follow-up examination after the resection, contrast-enhanced computed tomography (CT) and gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) showed arterially hyper-enhanced neoplastic lesions in the segment VI and VIII of the liver. Partial resections of the liver were performed 53 months after the initial surgery. At the 6th month follow-up examination from the second surgery, one and two tumors located in the liver segment III, and VIII, respectively, were detected by contrast-enhanced CT and Gd-EOB-DTPA-enhanced MRI. Anterior segmentectomy and partial resection of the segment III were performed 66 months after the initial surgery and 13 months after the second, respectively. The tumors were pathologically diagnosed as liver metastases of pancreatic SCN synonymous with serous cystadenocarcinoma. She remains disease-free without recurrence 6.5 years after the last operation., Conclusions: This is the first report of a case of metastatic SCN associated with VHL. Surgical resection might confer a favorable prognosis in patients of pancreatic SCN with liver metastases.

The mitogen-activated protein kinase (MAPK) pathway plays an important role in the colorectal cancer (CRC) progression, being supposed to be activated by the gene mutations, such as BRAF or KRAS. Although the inhibitors of extracellular signal-regulated kinase (ERK) have demonstrated efficacy in the cells with the BRAF or KRAS mutations, a clinical response is not always associated with the molecular signature. The patient-derived organoids (PDO) have emerged as a powerful in vitro model system to study cancer, and it has been widely applied for the drug screening. The present study aims to analyze the association between the molecular characteristics which analyzed by next-generation sequencing (NGS) and sensitivity to the ERK inhibitor (i.e., SCH772984) in PDO derived from CRC specimens. A drug sensitivity test for the SCH772984 was conducted using 14 CRC cell lines, and the results demonstrated that the sensitivity was in agreement with the BRAF mutation, but was not completely consistent with the KRAS status. In the drug sensitivity test for PDO, 6 out of 7 cases with either BRAF or KRAS mutations showed sensitivity to the SCH772984, while 5 out of 6 cases of both BRAF and KRAS wild-types were resistant. The results of this study suggested that the molecular status of the clinical specimens are likely to represent the sensitivity in the PDOs but is not necessarily absolutely overlapping. PDO might be able to complement the limitations of the gene panel and have the potential to provide a novel precision medicine., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aim: Crohn's disease (CD) can affect any part of the gastrointestinal tract; however, the frequency of CD lesions differs by location. This work aimed to examine resection rates by location to clarify locational characteristics of the small intestine in surgical CD cases., Method: This was a single-centre retrospective case note review of patients who had undergone resection for CD affecting the small intestine between January 2014 and February 2020. Operative details, including length of the small intestine, location and extent of the resection, identified the pattern of disease. By normalizing these data the resection rate along the length of the intestine was calculated to create resection rate curves., Results: One hundred and twenty six surgical cases were identified. The resection rate curves could be divided into two types: exponential and bimodal. For primary surgery, this depended on whether or not surgery was limited to an ileocolic resection. At subsequent surgery, a previous ileocaecal resection influenced the pattern of disease. The peaks of the bimodal curve were located at the proximal and distal ileum., Conclusion: CD patients requiring resection of the small intestine can be divided into terminal ileum type (exponential type) and proximal ileum type (bimodal type). In the future this analytical method may help predict the site of any recurrent disease but also provides a new perspective on the disease., (© 2020 The Association of Coloproctology of Great Britain and Ireland.)

We developed a novel technology using the photoacoustic effect that improve needle tip visibility. We evaluated whether this technology improves needle tip visibility when performing a deep peripheral nerve block in a cadaver model. A photoacoustic needle was developed using a conventional echogenic needle with an intraluminal optical fiber. A pulsed laser sends light from a source through the fiber, which is converted to ultrasound at the needle tip using the photoacoustic effect. A nerve block expert performed deep nerve blocks using the photoacoustic needle and the ultrasound views recorded, with or without photoacoustic ultrasound at the needle tip. Needle tip visibility was evaluated by questionnaire (Likert scale 1: very poor, 5: very good) completed by anesthesiologists evaluating recorded images. The score was presented as median [first quartile, third quartile]. Statistical analysis was performed using the Wilcoxon matched-pairs signed rank test. The scores of needle tip visibility with photoacoustic ultrasound from the needle tip (4.3 [4.0, 4.5]) was significantly higher than that without photoacoustic ultrasound (3.5 [3.2, 3.8]) (p < 0.01). Ultrasound emitted at the needle tip using the photoacoustic effect improves needle tip visibility during deep peripheral nerve blocks.Clinical trial number University Hospital Medical Information Network Center Clinical Trials Registration System (UMIN000036974).