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Purpose: Real-world, large-scale studies on the association between immune-related adverse events (irAE) and immune checkpoint inhibitor therapy effectiveness are limited. We evaluated overall survival (OS) and progression-free survival based on the occurrence and grade of irAEs., Patients and Methods: We used data from Japanese patients with unresectable advanced or recurrent non-small cell lung cancer (NSCLC) who received atezolizumab and were enrolled in J-TAIL, a multicenter, prospective, single-arm observational study., Results: Among the 1,002 patients, 190 (19.0%) developed irAEs. The most common irAEs were skin disorders (3.8%) of any grade and interstitial lung disease (1.5%) of grade ≥3. Patients who developed irAEs within 4 or 6 weeks of treatment initiation had higher baseline C-reactive protein levels than those without irAEs. OS was longer in patients with irAEs [HR, 0.66; 95% confidence interval (CI), 0.54-0.82], particularly in those with low-grade irAEs (HR, 0.45; 95% CI, 0.33-0.62), than in patients without irAEs. The HR (95% CI) for OS in patients with low-grade and high-grade skin or endocrine disorder-related irAEs was 0.42 (0.28-0.64) and 0.37 (0.15-0.88), respectively. The HR (95% CI) for OS in patients with low-grade and high-grade irAEs other than skin or endocrine disorders was 0.44 (0.30-0.65) and 1.27 (0.96-1.69), respectively., Conclusions: In patients with unresectable advanced or recurrent NSCLC treated with atezolizumab in real-world settings, irAEs are associated with a clinical benefit except in those with high-grade irAEs other than skin and endocrine disorders., Significance: Immune checkpoint inhibitors are useful for treating NSCLC but can cause life-threatening irAEs. This study had a large sample size and stratified the analysis by irAE type and grade. The results suggest that improved management of irAEs may improve the therapeutic effect of atezolizumab., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: The survival benefit of adjuvant chemotherapy after surgical resection of oligometastases from colorectal cancer (CRC) remains unclear. The prognostic role of circulating-tumor DNA (ctDNA) was reported recently and a risk stratification strategy based on monitoring minimal/molecular residual disease (MRD) has been proposed, however, which drug regimen is most effective for ctDNA-positive patients is unknown., Methods/design: Oligometastatic CRC patients planning to undergo surgery were registered in this study. After metastasectomy, the registered patients were enrolled in the treatment arm, in which 8 courses of modified-FOLFOXIRI (mFOLFOXIRI; irinotecan 150 mg/m 2 , oxaliplatin 85 mg/m 2 , l-leucovorin (l-LV) 200 mg/m 2 , and 46-h continuous infusion of 5-fluorouracil (5-FU) 2400 mg/m 2 every 2 weeks) followed by 4 courses of 5-FU/l-LV are administered. The patients who did not meet the eligibility criteria for the treatment arm or did not consent to mFOLFOXIRI enrolled in the observation arm in which standard of care treatment is provided. Prospective blood collections for retrospective ctDNA analysis are scheduled pre-surgery, and at 28 days, 4 and 7 months after surgery. The primary endpoint is treatment compliance at 8 courses of mFOLFOXIRI and the key secondary endpoints are the ctDNA-positivity rate and survival outcomes in ctDNA-positive and -negative groups. A total of 85 patients will be enrolled from 11 institutions. First patient-in was on July 2020. Accrual completed in February 2024., Discussion: This study will potentially identify a better treatment strategy for patients with resectable oligometastatic CRC having postsurgical ctDNA positivity, compared to the current standard of care approaches., Competing Interests: Conflicts of Interest Kozo Kataoka receives honoraria from Merck, Takeda, and Eli Lilly, and research grant from Japanese Society of Clinical Oncology. Kentaro Yamazaki receives lecture fees from Merck Biopharma, Takeda, Chugai, Taiho, Yakult, Ono, Eli Lily, MSD and Bristol. Keita Mori receives lecture fees from Chugai, Ono, Daiichi Sankyo and Eli Lilly. Nobuhisa Matsuhashi receives honoraria from Abbott, AMCO, Asahi Kasei Pharma, AstraZeneca, Bayer Yakuhin, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, EA Pharma, Eisai, Eli Lilly, Gunze Medical Limited, Kaken Pharm., Kyowa Kirin, MC Medical, Merck Biopharma, Miyarisan Pharm., MSD, Novartis, Ono, Taiho, Takeda Pharm., TERUMO, Tsumura, Viatris, Yakult Honsha; research funding from Daiichi Sankyo, EP-CRSU, EPS Corporation, MSD, Ono Pharm., ShiftZero K.K., Taiho Pharm. Masahiro Goto receives honoraria from Daiichi Sankyo, MSD, Taiho, and Ono Pharm and research funding from Taiho, Chugai Pharma and Nippon Kayaku. Manabu Shiozawa received lecture fees from Merck Biopharma, Takeda, Yakult Honsha, Ono Pharmaceutical, and Eli Lilly. Shruti Sharma, Joe Ensor, Adham Jurdi and Minetta C. Liu are employees at Natera, Inc. with stock or option to own stock. Minetta C. Liu received grants (funding to Mayo Clinic) from Eisai, Exact Sciences, Genentech, Genomic Health, GRAIL, Menarini Silicon Biosystems, Merck, Novartis, Seattle Genetics, and Tesaro; travel support from AstraZeneca, Genomic Health, and Ionis; and Ad hoc advisory board meetings (all funds to Mayo Clinic): AstraZeneca, Celgene, Roche/Genentech, Genomic Health, GRAIL, Ionis, Merck, Pfizer, Seattle Genetics, Syndax. Masataka Ikeda receives honoraria from Taiho, Bayer, Pfizer, and consulting fee from Daiichi Sankyo. The remaining authors have declared no conflict of interest., (Copyright © 2024 The Japan Society of Coloproctology.)

Background: Spatial and temporal heterogeneities of RAS and other molecular genes should be considered in the treatment of metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs); acquired RAS mutation is sometimes observed at disease progression of treatment with the anti-EGFR mAb. At the same time, discrepancy of RAS status from tissues and circulating tumor DNA (ctDNA) in the same patient is sometimes observed. Based on this, we commenced two observational studies to clarify these heterogeneities of RAS and BRAF in mCRC, using next generation sequencing from liquid biopsy., Methods/design: RAS-trace study is an observational study to monitor ctDNA RAS/BRAF/PIK3CA status every 4-12 weeks using the Plasma-SeqSensei™ CRC RUO Kit (Sysmex Inostics GmbH) in mCRC with RAS/BRAF wild-type (wt) on tumor tissue. The primary endpoint was the time to the acquired RAS mutations. A total of 42 patients has been accrued. RAS-trace-2 study is also an observational study aimed at comparing the efficacy of the anti-EGFR mAb in ctDNA RAS/BRAF wt with ctDNA RAS or BRAF mutant mCRC patients, whose RAS/BRAF are wt in tumor tissue. The primary endpoint was progression-free survival in patients with ctDNA RAS/BRAF wt and RAS or BRAF mutant. A total of 240 patients will be accrued over 2 years., Discussion: These trials will help us understanding the clinical significance of spatial and temporal heterogeneities of RAS, BRAF and other genes, while optimizing the anti-EGFR mAb treatment strategies in mCRC., Competing Interests: Conflicts of Interest KK received lecture fees from Merck, Takeda, and Eli Lilly, and research funds from Sysmex Corporation. JF is an employee of the Sysmex Inostics GmbH. MS received lecture fees from Merck, Takeda, Yakult, Ono, and Eli Lilly. JW received lecture fees from Eli Lilly and Takeda. TK received lecture fees from Daiichi Sankyo, Taiho, Bristol-Myers Squibb, Ono, and Eli Lilly. NM received lecture fees from Takeda and scholarship endowments from Yakult. KY received lecture fees from Merck, Takeda, Chugai, Taiho, Yakult, Ono, Eli Lily, MSD and Bristol. KM received lecture fees from Chugai, Ono, Daiichi Sankyo and Eli Lilly. The rest of the authors do not have any conflicts of interest., (Copyright © 2024 The Japan Society of Coloproctology.)

Background: Primary cardiac angiosarcomas are extremely rare and their prognosis is poor. Surgical resection is the first-line treatment; however, no clear standard of care has been clearly established because of the rarity of these tumors., Case Presentation: A 61-year-old man who had presented with dyspnea on exertion was referred to our hospital. Contrast-enhanced computed tomography revealed massive pericardial effusion and a 40-mm enhanced mass adherent to the anterior wall of the right atrium and involving the right coronary artery. Having diagnosed the mass as a cardiac tumor, we resected the mass under the guidance of epi-cardiac echocardiography guidance, which showed continuity between the tumor and the right atrium, reconstructed the right atrial free wall with a bovine pericardial patch, and performed coronary artery bypass grafting to the right coronary artery using the great saphenous vein. The right atrial wall was resected with adequate tumor-free margin. On the right ventricular side, we resected the right atrial wall 1 cm from the tumor, 2 cm from the atrioventricular groove. Because hemodynamic deterioration occurred after aortic declamping, intra-aortic balloon pumping and veno-arterial extracorporeal membrane oxygenation were instituted. Postoperatively, circulatory support devices were removed safely, and the patient was discharged on the 25th postoperative day. Histopathological examination of the surgical specimens resulted in a diagnosis of angiosarcoma, with positive surgical margins. Chemotherapy and radiotherapy (69 Gy in 30 fractions) were therefore initiated after discharge. To date, the patient has been alive and well with no recurrence of tumor for 4 years and 10 months since surgery., Discussion: This case study suggests the usefulness of multimodality treatment comprising surgical resection and adjuvant therapy, for cardiac angiosarcoma., (© 2023. The Author(s).)

PIWI-interacting RNAs (piRNAs) repress transposons to protect the germline genome from DNA damage caused by transposon transposition. In Drosophila , the Traffic jam ( Tj ) mRNA is consumed to produce piRNA in its 3'-UTR. A cis element located within the 3'-UTR, Tj-cis , is necessary for piRNA biogenesis. In this study, we analyzed the structure of the Tj-cis RNA, a 100-nt RNA corresponding to the Tj-cis element, by the SHAPE and NMR analyses and found that a stable hairpin structure formed in the 5' half of the Tj-cis RNA. The tertiary structure of the 16-nt stable hairpin was analyzed by NMR, and a novel stem-loop structure, the T-hairpin, was found. In the T-hairpin, four uridine residues are exposed to the solvent, suggesting that this stem-loop is the target of Yb protein, a Tudor domain-containing piRNA biogenesis factor. The piRNA biogenesis assay showed that both the T-hairpin and the 3' half are required for the function of the Tj-cis element, suggesting that both the T-hairpin and the 3' half are recognized by Yb protein., (© 2022 Takase et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.)

Entropy generation from a mechanical and thermal perspective are quantitatively compared via molecular dynamic (MD) simulations and mechanical and thermal experiments. The entropy generation values regarding mechanical tensile loading-which causes invisible damage-of the Polyamide 6 (PA6) material are discussed in this study. The entropy values measured mechanically and thermally in the MD simulation were similar. To verify this consistency, mechanical and thermal experiments for measuring entropy generation were conducted. The experimentally obtained mechanical entropy was slightly less than that calculated by MD simulation. The thermal capacity is estimated based on the specific heat capacity measured by differential scanning calorimetry (DSC), applying the assumed extrapolation methods. The estimated entropy generation was higher than the aforementioned values. There is a possibility that the entropy-estimating method used in this study was inappropriate, resulting in overestimations. In any case, it is verified that entropy increases with mechanical loading and material invisible damage can be qualitatively detected via thermal property measurements.

Background: Gastrobronchial fistulas are rare, but life-threatening, complications of esophagectomy. They are caused by anastomotic leakage and mainly occur around anastomotic sites. In the present paper, we report a rare case of leakage from the staple line of a gastric tube after esophagectomy for esophageal cancer, which was successfully treated using an intercostal muscle flap and lung resection., Case Presentation: A 61-year-old male underwent subtotal esophagectomy with regional lymphadenectomy for esophageal cancer. The sutures along the staple line of the gastric tube failed 11 days after surgery, and a pulmonary abscess was also found on imaging. The abscess did not heal after conservative treatment; therefore, right lower lobectomy, gastrobronchial fistula resection, primary closure, and patching of the leaking portion of the gastric tube with an intercostal muscle flap were performed 9 months after the first operation. The patient's postoperative course was uneventful, and he was discharged on the 354th day., Conclusions: We experienced a case involving a gastrobronchial fistula caused by leakage from the staple line of a gastric tube and successfully treated it by performing right lower lobectomy and patching the leak with an intercostal muscle flap.

Herein, the stress-state dependence of fracture entropy for a polyamide 6 material is investigated through molecular dynamics simulations. Although previous research suggests that a constant entropy increase can be universally applied for the definition of material fracture, the dependence of stress triaxiality has not yet been discussed. In this study, entropy values are evaluated by molecular dynamics simulations with varied combined stress states. The calculation is implemented using the 570,000 all-atom model. Similar entropy values are obtained independently of stress triaxiality. This study also reveals the relationship between material damage, which is correlated with void size, and the entropy value.

Purpose: The influence of anastomotic leakage on long-term survival in patients with rectal cancer is debatable. The aim of this study was to evaluate relationships between anastomotic leakage and long-term survival., Methods: In this multicenter retrospective cohort study, 395 consecutive stage I to III rectal cancer patients underwent anterior resection between 2007 and 2012. Five-year overall survival, 5-year disease-free survival, and 5-year local recurrence-free survival were compared between patients with leakage (Leakage (+)) and patients without leakage (Leakage (-))., Results: Of 395 patients, 50 (12.7%) had anastomotic leakage. Of these 50, 34 (68.0%) required urgent surgery and 16 (32.0%) could be managed by watchful waiting or with percutaneous drainage. The median follow-up period was 62.6 months. Five-year overall survival did not differ between the two groups (Leakage (+) 93.8% vs. Leakage (-) 89.0%, P = 0.121). Five-year disease-free survival also did not differ between the two groups (81.6% vs. 80.3%, P = 0.731), and neither did 5-year local recurrence-free survival (91.9% vs. 86.1%, P = 0.206). In a multivariable Cox regression model, BMI > 25, preoperative CA19-9 > 37, pathological T stage, pathological N stage, and circumferential resection margin (CRM) positive were independent predictors of disease-free survival. Moreover, pathological T stage, pathological N stage, and CRM positive were the only independent predictors of overall survival and local recurrence-free survival. Anastomotic leakage was not a risk factor for overall survival, disease-free survival, or local recurrence-free survival., Conclusion: Anastomotic leakage is not associated with a significant decrease in long-term survival in rectal cancer patients.

The excessive intake of phosphate (Pi), or chronic kidney disease (CKD), can cause hyperphosphatemia and eventually lead to ectopic calcification, resulting in cerebrovascular diseases. It has been reported that reactive oxygen species (ROS), induced by high concentrations of Pi loading, play a key role in vascular calcification. Therefore, ROS suppression may be a useful treatment strategy for vascular calcification. 12AC3O is a newly synthesized gem -dihydroperoxide (DHP) that has potent antioxidant effects. In the present study, we investigated whether 12AC3O inhibited vascular calcification via its antioxidative capacity. To examine whether 12AC3O prevents vascular calcification under high Pi conditions, we performed Alizarin red and von Kossa staining, using the mouse aortic smooth muscle cell line p53LMAco1. Additionally, the effect of 12AC3O against oxidative stress, induced by high concentrations of Pi loading, was investigated using redox- sensitive dyes. Further, the direct trapping effect of 12AC3O on reactive oxygen species (ROS) was investigated by ESR analysis. Although high concentrations of Pi loading exacerbated vascular smooth muscle calcification, calcium deposition was suppressed by the treatment of both antioxidants and 12AC3O, suggesting that the suppression of ROS may be a candidate therapeutic approach for treating vascular calcification induced by high concentrations of Pi loading. Importantly, 12AC3O also attenuated oxidative stress. Furthermore, 12AC3O directly trapped superoxide anion and hydroxyl radical. These results suggest that ROS are closely involved in high concentrations of Pi-induced vascular calcification and that 12AC3O inhibits vascular calcification by directly trapping ROS.

Introduction: The aim of this trial was to investigate whether a digital device that provides real-time visualized brushing instructions would contribute to the removal of dental plaque over usual brushing instructions., Methods: We conducted a single-center, parallel-group, stratified permuted block randomized control trial with 1:1 allocation ratio. Eligibility criteria included people aged ≥ 18 years, and exclude people who met the following criteria: severely crowded teeth; using interdental cleaning implement; having external injury in the oral cavity, or stomatitis; having less than 20 teeth; using orthodontic apparatus; visited to a dental clinic; having the possibility of consulting a dental clinic; having a dental license; not owning a smartphone or tablet device; smoker; taken antibiotics; pregnant; an allergy to the staining fluid; and employee of Sunstar Inc. All participants received tooth brushing instructions using video materials and were randomly assigned to one of two groups for four weeks: (1) an intervention group who used the digital device, providing real-time visualized instructions by connection with a mobile application; and (2) a control group that used a digital device which only collected their brushing logs. The primary outcome was the change in 6-point method plaque control record (PCR) score of all teeth between baseline and week 4. The t-test was used to compare the two groups in accordance with intention-to-treat principles., Results: Among 118 enrolled individuals, 112 participants were eligible for our analyses. The mean of PCR score at week 4 was 45.05% in the intervention group and 49.65% in the control group, and the change of PCR score from baseline was -20.46% in the intervention group and -15.77% in the control group (p = 0.088, 95% confidence interval -0.70-10.07)., Conclusions: A digital device providing real-time visualized brushing instructions may be effective for the removal of dental plaque., Competing Interests: The authors have read the journal’s policy, and the authors have the following competing interests to declare: NT, MN, and YO are employees of Sunstar Inc. (manufacturer of GUMPLAY, the study device in this project). GUMPLAY has been on the market since before the start of research. It was supplied and used to conduct the study, however, there was no other conflict of interest to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development associated with this research to declare.

Background: Esophagectomy with extended lymphadenectomy remains the mainstay of treatment for localized esophageal cancer. Currently, transthoracic and abdominal esophagectomy with cervical anastomosis (McKeown esophagectomy) is a frequently used technique in Japan. However, cervical anastomosis is still an invasive procedure with a high incidence of anastomotic leakage. The use of a drainage tube to treat anastomotic leakage is effective, but the routine placement of a closed suction drain around the anastomosis at the end of the operation remains controversial. The objective of this study is to evaluate the postoperative anastomotic leakage rate, duration to oral intake, hospital stay, and analgesic use with nonplacement of a cervical drainage tube as an alternative to placement of a cervical drainage tube., Methods: This is an investigator-initiated, investigator-driven, open-label, randomized controlled parallel-group, noninferiority trial. All adult patients (aged ≥20 and ≤85 years) with histologically proven, surgically resectable (cT1-3 N0-3 M0) squamous cell carcinoma, adenosquamous cell carcinoma, or basaloid squamous cell carcinoma of the intrathoracic esophagus, and European Clinical Oncology Group performance status 0, 1, or 2 are assessed for eligibility. Patients (n = 110) with resectable esophageal cancer who provide informed consent in the outpatient clinic are randomized to either nonplacement of a cervical drainage tube (n = 55) or placement of a cervical drainage tube (n = 55). The primary outcome is the percentage of Clavien-Dindo grade 2 or higher anastomotic leakage., Discussion: This is the first randomized controlled trial comparing nonplacement versus placement of a cervical drainage tube during McKeown esophagectomy with regards to the usefulness of a drain for anastomotic leakage. If our hypothesis is correct, nonplacement of a cervical drainage tube will be recommended because it is associated with a similar anastomotic leakage rate but less pain than placement of a cervical drainage tube., Trial Registration: UMIN-CTR, 000031244. Registered on 1 May 2018.

Mirror image is one of the most difficult situations that the assistant surgeon encounters in laparoscopic colorectal surgery. The aim of the present study was to investigate whether task performance with mirror images improves by changing the position of the monitor and the rotation angle of the camera. Twenty-four surgeons performed the task under different conditions: Coaxial image (C), Mirror image (M), Mirror image + Monitor on the left side of participants (M + Mon), Mirror image + Camera rotated 90 degrees to the right (M + Cam), and Mirror image + Monitor on the left side + Camera rotated to the right (M + Mon + Cam) in a training box. The outcome measure was the mean time for completing the task. The mean time for completing the task, in decreasing order, was M (111.4 ± 58.9 seconds) > M + Mon (70.5 ± 29.4 seconds) > M + Cam (47.1 ± 17.1 seconds) > M + Mon + Cam (33.4 ± 10.3 seconds) > C (20.5 ± 3.5 seconds). (multivariable analysis of variance (MANOVA), p = 7.9 × 10 -7 ) Task performance with mirror images improved by changing the monitor positioning and camera rotation angle. This novel method is a simple way to overcome mirror image in laparoscopic colorectal surgery.

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive tumor with frequent recurrence even after curative resection. The tumor microenvironment, which consists of non-cancer cells, such as cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), was recently reported to promote several cancers, including ESCC. However, the role of CAF as a coordinator for tumor progression in ESCC remains to be elucidated. In our immunohistochemical investigation of ESCC tissues, we observed that the intensity of expression of two CAF markers-alpha smooth muscle actin (αSMA) and fibroblast activation protein (FAP)-in the tumor stroma was significantly correlated with the depth of tumor invasion, lymph node metastasis, advanced pathological stage, and poor prognosis. We co-cultured human bone marrow-derived mesenchymal stem cells (MSCs) with ESCC cells and confirmed the induction of FAP expression in the co-cultured MSCs. These FAP-positive MSCs (which we defined as CAF-like cells) promoted the cell growth and migration of ESCC cells and peripheral blood mononuclear cell-derived macrophage-like cells. CAF-like cells induced the M2 polarization of macrophage-like cells. A cytokine array and ELISA revealed that CAF-like cells secreted significantly more CCL2, Interleukin-6, and CXCL8 than MSCs. These cytokines promoted the migration of tumor cells and macrophage-like cells. The silencing of FAP in CAF-like cells attenuated cytokine secretion. We compared cell signaling of MSCs, CAF-like cells, and FAP-silenced CAF-like cells; PTEN/Akt and MEK/Erk signaling were upregulated and their downstream targets, NF-κB and β-catenin, were also activated with FAP expression. Silencing of FAP attenuated these effects. Cytokine secretion from CAF-like cells were attenuated by inhibitors against these signaling pathways. These findings indicate that the collaboration of CAFs with tumor cells and macrophages plays a pivotal role in tumor progression, and that FAP expression is responsible for the tumor promotive and immunosuppressive phenotypes of CAFs.

Purpose: Although optical coherence tomography (OCT) is essential for ophthalmologists, reading of findings requires expertise. The purpose of this study is to test deep learning with image augmentation for automated detection of chorioretinal diseases., Methods: A retina specialist diagnosed 1,200 OCT images. The diagnoses involved normal eyes ( n =570) and those with wet age-related macular degeneration (AMD) ( n =136), diabetic retinopathy (DR) ( n =104), epiretinal membranes (ERMs) ( n =90), and another 19 diseases. Among them, 1,100 images were used for deep learning training, augmented to 59,400 by horizontal flipping, rotation, and translation. The remaining 100 images were used to evaluate the trained convolutional neural network (CNN) model., Results: Automated disease detection showed that the first candidate disease corresponded to the doctor's decision in 83 (83%) images and the second candidate disease in seven (7%) images. The precision and recall of the CNN model were 0.85 and 0.97 for normal eyes, 1.00 and 0.77 for wet AMD, 0.78 and 1.00 for DR, and 0.75 and 0.75 for ERMs, respectively. Some of rare diseases such as Vogt-Koyanagi-Harada disease were correctly detected by image augmentation in the CNN training., Conclusion: Automated detection of macular diseases from OCT images might be feasible using the CNN model. Image augmentation might be effective to compensate for a small image number for training.

Esophagectomy with extended lymphadenectomy remains the mainstay of treatment for localized esophageal cancer. However, it is one of the most invasive procedures with high morbidity. To reduce invasiveness, minimally invasive esophagectomy (MIE), which includes thoracoscopic, laparoscopic, mediastinoscopic, and robotic surgery, is becoming popular worldwide. Thoracoscopic esophagectomy in the prone position is ergonomic for the surgeon and has better perioperative arterial oxygen pressure/fraction of inspired oxygen (P/F) ratio. Thoracoscopic esophagectomy in the left decubitus position is easy to introduce because it is similar to standard right posterolateral open esophagectomy (OE) in position. It has a relatively short operative time. Laparoscopic approach could potentially have a substantial effect on pneumonia prevention under the condition of thoracotomy. Mediastinoscopic surgery has the potential to reduce pulmonary complications because it can avoid a transthoracic procedure. In robotic surgery, in the future, less recurrent laryngeal nerve palsy will be expected as a result of polyarticular fine maneuvering without human tremors. In studies comparing MIE with OE, mediastinoscopic surgery and robotic surgery are usually not included; these studies show that MIE has a longer operative time and less blood loss than OE. MIE is particularly beneficial in reducing postoperative respiratory complications such as atelectasis, despite no dramatic decrease in pneumonia. Reoperation might occur more frequently with MIE. There is no significant difference in mortality rate between MIE and OE. It is important to recognize that the advantages of MIE, particularly "less invasiveness", can be of benefit at facilities with experienced medical personnel., Competing Interests: Authors declare no conflicts of interest for this article.

Age-related macular degeneration (AMD) is a leading cause of blindness in people over 50 years of age in many developed countries. Drusen are yellowish extracellular deposits beneath retinal pigment epithelium (RPE) found in aging eyes and considered as a biomarker of AMD. However, the biogenesis of drusen has not been elucidated. We reported previously that multicellular spheroids of human RPE cells constructed a well-differentiated monolayer of RPE with a Bruch's membrane. We determined that RPE spheroids exhibited drusen formation between the RPE and Bruch's membrane with expression of many drusen-associated proteins, such as amyloid β and complement components, the expression of which was altered by a challenge with oxidative stress. Artificial lipofuscin-loaded RPE spheroids yielded drusen more frequently. In the current study, we showed that drusen originates from the RPE. This culture system is an attractive tool for use as an in vitro drusen model, which might help elucidate the biogenesis of drusen and the pathogenesis of related diseases, such as AMD., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

Tumor-associated macrophages (TAMs) are involved in tumor progression and poor prognosis in several malignancies. We previously demonstrated the interaction between high numbers of infiltrating TAMs and poor prognosis in esophageal squamous cell carcinomas (ESCCs). To investigate the significance of TAMs in ESCC, we conducted a cDNA microarray analysis of peripheral blood monocytes (PBMo)-derived macrophages and PBMo-derived macrophages stimulated with conditioned media of TE-series ESCC cell lines (TAM-like PBMo-derived macrophages). C-X-C motif chemokine ligand 8 ( CXCL8 ) was up-regulated in the TAM-like PBMo-derived macrophages. Here we confirmed a high expression level of CXCL8 in TAM-like PBMo-derived macrophages and the expression of CXCR1/2, known as CXCL8 receptors, in TE-series ESCC cell lines. Recombinant human CXCL8 induced the ESCC cell lines' migration and invasion by the phosphorylation of Akt and Erk1/2. In indirect co-cultures, not only signal pathway inhibitors but also neutralizing antibodies against CXCL8, CXCR1 and CXCR2 suppressed these phenotypes induced by TAM-like PBMo-derived macrophages. Immunohistochemical analysis of 70 resected ESCC samples showed that high expression levels of CXCL8 in ESCC tissues were significantly associated with lymph node metastasis and poor prognosis. These results suggest that CXCL8 up-regulated in the microenvironment may contribute to ESCC progression by promoting cancer cells' migration and invasion., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

PiT-1 (encoded by SLC20A1) and PiT-2 (encoded by SLC20A2) are type-III sodium-dependent phosphate cotransporters (NaPiTs). Recently, SLC20A2 mutations have been found in patients with idiopathic basal ganglia calcification (IBGC), and were predicted to bring about an inability to transport Pi from the extracellular environment. Here we investigated the effect of low Pi loading on the human neuroblastoma SH-SY5Y and the human glioblastoma A172 cell lines. The results show a different sensitivity to low Pi loading and differential regulation of type-III NaPiTs in these cells. We also examined whether 5-aminolevulinic acid (5-ALA) inhibited low Pi loading-induced neurotoxicity in SH-SY5Y cells. Concomitant application of 5-ALA with low Pi loading markedly attenuated low Pi-induced cell death and mitochondrial dysfunction via the induction of HO-1 by p38 MAPK. The findings provide us with novel viewpoints to understand the pathophysiology of IBGC, and give a new insight into the clinical prevention and treatment of IBGC.

Among the various diagnostic modalities for small bowel hemangioma, video capsule endoscopy (VCE) and double-balloon enteroscopy (DBE) can be recommended as part of the work-up in patients with obscure gastrointestinal bleeding (OGIB). DBE is superior to VCE in the accuracy of diagnosis and therapeutic potential, while in most cases total enteroscopy cannot be achieved through only the antegrade or retrograde DBE procedures. As treatment for small bowel bleeding, especially spout bleeding, localization of the lesion for the decision of DBE insertion facilitates early treatment, such as endoscopic hemostatic clipping, allowing patients to avoid useless transfusion and the worsening of their disease into life-threatening status. Applying endoscopic India ink marking prior to laparoscopic surgical resection is a particularly useful technique for more minimally invasive treatment. We report two cases of small bowel hemangioma found in examinations for OGIB that were treated with combination of laparoscopic and endoscopic modalities., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest associated with this manuscript.

Purpose: To study the association between the distributions of microaneurysms detected by en face optical coherence tomography angiography (OCTA) and diabetic macular edema (DME)., Methods: The study design was a retrospective chart review of 27 patients (33 eyes) with DME. The eyes were scanned using OCTA (6 × 6 mm) and spectral-domain (SD) OCT macular cube. Each of the images of the capillary plexus was overlaid onto the image of the topographic map, and the densities of the microaneurysms were measured by ImageJ software. The association between the distribution of microaneurysms and macular edema was evaluated., Results: For microaneurysms in areas with and without edema, 77.3 ± 8.1% of these microaneurysms were located in the deep capillary plexuses (DCP). However, in areas of edema where the retinal thickness was more than 400 μm, 91.3 ± 9.1% of the microaneurysms were found in the DCP. This difference was statistically significant (P < 0.001). In the macular edema area, there was a significantly higher density of microaneurysms in the DCP compared to the superficial capillary plexuses (1.71/mm2 vs. 0.17/mm2, P < 0.001). There was also a significant correlation between the macular volume and the density of microaneurysms in the DCP in edema (r = 0.63, P < 0.001)., Conclusions: Our study demonstrated a high proportion of microaneurysms in the DCP, as well as a novel association between the distributions of microaneurysms detected by OCTA and DME. Results also indicated that microaneurysms located in the DCP contribute to the pathogenesis of DME.

Tumor-associated macrophages (TAMs) are known to be involved in the progression, angiogenesis, and motility of various cancers. We previously reported the association between an increased number of infiltrating TAMs with tumor progression and poor prognosis in esophageal squamous cell carcinomas (ESCCs). To study the roles of TAMs in ESCC, we first exposed peripheral blood monocyte (PBMo)-derived macrophages from healthy volunteers to conditioned media of TE series human ESCC cell line (TECM) and confirmed the induction of the expression of the M2 macrophage marker CD204 and the protumorigenic factors interleukin (IL)-10, VEGFA, and MMPs. Next, we compared gene expression profiles between PBMo-derived macrophages stimulated with or without TECM by cDNA microarray and focused on growth differentiation factor 15 (GDF15) among the highly expressed genes including IL-6, IL-8, and CXCL1. Our immunohistochemical study of 70 surgically resected ESCCs revealed that GDF15 was present not only in cancer cells but also in macrophages. The high expression of GDF15 in the ESCCs was significantly correlated with several more malignant phenotypes including vessel invasion, lymph node metastasis, and clinical stages. Patients with high GDF15 expression showed significantly poorer disease-free survival (P=0.011) and overall survival (P=0.041). We also found that recombinant human GDF15 promotes cell proliferation and the phosphorylation of both Akt and Erk1/2 in ESCC cell lines in vitro. These results indicate that GDF15 is secreted by both TAMs and cancer cells in the tumor microenvironment and is associated with aberrant growth and a poor prognosis in human ESCC.

Tumor-associated macrophages (TAMs) are known to be involved in the progression of various human malignancies. We previously demonstrated that CD204 was a useful marker for TAMs contributing to the angiogenesis, progression, and prognosis of human esophageal squamous cell carcinoma (ESCC). We also showed that conditioned media of ESCC cell lines induced CD204 expression in THP-1 human monocytic leukemia cells. Here, we performed a cDNA microarray analysis between THP-1 cells stimulated with TPA (macrophage [MΦ]-like THP-1 cells) treated with and without conditioned medium of ESCC cell line to clarify the molecular characteristics of TAMs in ESCC. From the microarray data, we discovered that Cyr61 was induced in CD204-positive-differentiated THP-1 cells (TAM-like THP-1 cells). In the ESCC microenvironment, not only cancer cells but also TAMs expressed Cyr61. Interestingly, the expression levels of Cyr61 showed a significant positive correlation with the number of CD204-positive macrophages in ESCCs by immunohistochemistry. Recombinant human Cyr61 (rhCyr61) promoted cell migration and induced the expression of CD204 along with the activation of the MEK/ERK pathway in MΦ-like THP-1 cells. Pretreatment with a MEK1/2 inhibitor significantly inhibited not only the Cyr61-mediated migration but also the CD204 expression in the MΦ-like THP-1 cells. These results suggest that Cyr61 may contribute to the expression of CD204 and the promotion of cell migration via the MEK/ERK pathway in TAMs in the ESCC microenvironment., (© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

A starch ingredient with antioxidative activity, as measured by the DPPH method, was produced by baking corn starch with an organic acid; it has been named ANOX sugar (antioxidative sugar). The baking temperature and time were fixed at 170 °C and 60 min, and the organic acid used was selected from preliminary trials of various kinds of acid. The phytic acid ANOX sugar preparation showed the highest antioxidative activity, but the color of the preparation was almost black; we therefore selected L-tartaric acid which had the second highest antioxidative activity. The antioxidative activity of the L-tartaric acid ANOX sugar preparation was stable against temperature, light, and enzyme treatments (α-amylase and glucoamylase). However, the activity was not stable against variations in water content and pH value. The antioxidative activity of ANOX sugar was stabilized by treating with boiled water or nitrogen gas, or by pH adjustment.

The purpose of this study was to examine the simultaneous interrelationships of oral health behavior and oral health between mothers and their children using the linear structural relations (LISREL) program. The subjects comprised 117 pairs of mothers and their children aged between 8 and 11 years. Dental status was expressed as DMFT. The Oral Rating Index (ORI) for mothers and ORI for children (ORI-C) were used as measures of gingival health. Hiroshima University Dental Behavioral Inventory (HU-DBI) was used for the assessment of mothers' oral health behavior. HU-DBI had a direct positive relationship to ORI, a direct negative relationship to DFT, and a direct positive association with ORI-C. Toothbrushing had a direct negative relationship to ORI-C. The hypothesized model was found to be closely consistent with the data. These results indicate that the periodontal health status of mothers is directly related to the oral health status of their children, and that toothbrushing by children is directly related to their gingival health.

We investigated sex and age group differences in attitudes to oral health among school-age children using an Oral Self-Care Appraisal (OSCA) to systematically determine changes in oral health knowledge, attitude, and behavior across developmental stages. The subjects (n = 1584) were stratified after random sampling so that each school grade analyzed contained 88 boys and 88 girls. Factor analysis was undertaken to identify a set of underlying factors, with 10 factors considered in the cross-sectional study. Our results showed that the factors toothbrushing, persistence, and sociability were more predominant in primary school children than in junior high and senior high school students. Furthermore, postponement of visiting the dentist and resignation to one's own dental cavities became more predominant in proportion to the level of school education. Girls had significantly higher scores than boys for desire to improve oral care, dental anxiety, dependency on snacks, toothbrushing, concern over number of cavities, and sociability. Together, the results indicated that the oral health care behavior of girls was better than that of boys, and that the tendency to postpone visiting the dentist and resignation to one's own dental cavities increased markedly with age.

We constructed a pig 3alpha/beta,20beta-hydroxysteroid dehydrogenase (3alpha/beta,20beta-HSD) mutant, which lacks 12 carboxyl-terminal amino acids residues. Enzyme activity studies indicated that the deleted amino acids have a role in steroid metabolism and may assist in substrate binding in wild-type 3alpha/beta,20beta-HSD. Furthermore, substrate binding likely induces a conformational change allowing the 12 carboxyl-terminal amino acids interact with the steroid substrate [Nakajin S. et al., Biochim. Biophys. Acta, 1550, 175-182 (2001)]. In this paper, we clarified that although pig 3alpha/beta,20beta-HSD is potently inhibited by dexamethasone, glycyrrhetinic acid and spironolactone, this inhibition is remarkably attenuated by deleting the 12 carboxyl-terminal residues. The inhibition constant (Ki) of pig 3alpha/beta,20beta-HSD for dexamethasone increased 115-fold. These observations also indicate that these amino acid residues interact with steroid substrates or steroid inhibitors and have an important role in substrate or inhibitor binding to the active site.

Pig 3alpha/beta,20beta-hydroxysteroid dehydrogenase is an NADPH-dependent enzyme that catalyses the reduction of ketones on steroids and aldehydes and ketones on various xenobiotics, like its homologue carbonyl reductase. 3alpha/beta,20beta-Hydroxysteroid dehydrogenase and carbonyl reductase are members of the short-chain dehydrogenases/reductase family, in which a tyrosine residue and a lysine residue have been identified as catalytically important. In pig 20beta-hydroxysteroid dehydrogenase these residues are tyrosine-194 and lysine-198. Here we report the effect on the reduction of two ketone and two aldehyde substrates by pig 3alpha/beta,20beta-hydroxysteroid dehydrogenase in which tyrosine-194 has been mutated to phenylalanine and cysteine, and lysine-198 has been mutated to isoleucine and arginine. Mutants with phenylalanine-194 or isoleucine-198 are inactive. Depending on the substrate, the mutant with cysteine-194 has a catalytic efficiency of 0.4-1% and the mutant with arginine-198 has a catalytic efficiency of 4-23% of the wild-type enzyme. We also mutated tyrosine-81 and tyrosine-253 to phenylalanine. Although both tyrosines are conserved in 3alpha/beta,20beta-hydroxysteroid dehydrogenase and carbonyl reductase, depending on the substrate, the mutant enzymes are as active as, or more active than, wild-type enzyme.

The carbonyl reductase activity exhibited by pig testicular 20 beta-hydroxysteroid dehydrogenase (20 beta-HSD) was examined using a recombinant enzyme. Kinetic parameters were obtained for 48 carbonyl group-containing substrates, including aromatic aldehydes, aromatic ketones, cycloketones, quinones, aliphatic aldehydes and aliphatic ketones. 20 beta-HSD showed a high affinity towards quinones, such as 9,10-phenanthrenequinone, alpha-naphthoquinone and menadione (Km values of 4, 2 and 5 microM, respectively), and the substrate utilization efficiency (Vmax/Km) of the enzyme against these quinones was very high. Cyclohexanone and 2-methylcyclohexanone were also reduced with a high Vmax/Km value, but not cyclopentanone or 2-methylcyclopentanone. Various aromatic aldehydes and ketones including benzaldehyde- and acetophenone-derivatives were reduced by 20 beta-HSD. Especially, 4-nitrobenzaldehyde and 4-nitroacetophenone were reduced with high Vmax/Km values in the related compounds. The enzyme also reduced the pyridine-derivatives, 2-, 3-, and 4-benzoylpyridine, with the Vmax/Km value for 2-benzoylpyridine being the highest. 20 beta-HSD reduced aliphatic aldehydes and aliphatic ketones, but was more effective on the former. The correlation between the structure of carbonyl compounds and their substrate Vmax/Km is discussed.