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Abstract Pheochromocytoma and paraganglioma (PPGL) represent a group of rare neuroendocrine tumors known for their potential to metastasize. This study provides a comprehensive retrospective evaluation of 15 patients diagnosed with metastatic or recurrent PPGL at our institution over a two-decade span (2000–2020). Our primary objectives were to delineate the long-term clinical outcomes and pinpoint key prognostic determinants. Median duration from initial PPGL diagnosis to the onset of metastasis or recurrence stood at 5.8 years. Predominant sites for metastasis included the bone, lung, lymph nodes, and peritoneum. A salient finding was that surgical interventions targeting metastatic lesions significantly improved prognosis. Further analysis revealed that a Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) exceeding 7 closely associated with unfavorable outcomes. These insights not only underscore the clinical variability of PPGL’s progression but also highlight the pivotal role of surgical management for metastatic or recurrent cases. The value of the PASS score as an informative prognostic tool was evident, suggesting its utility in shaping future therapeutic approaches. Given the intricacies of PPGL, collaborative studies involving larger patient cohorts will be crucial to optimize management strategies and prognostication.

Abstract The relationship between blood group and rebleeding in acute lower gastrointestinal bleeding (ALGIB) remains unclear. This study aimed to investigate the association between blood group O and clinical outcomes in patients with ALGIB. The study included 2336 patients with ALGIB whose bleeding source was identified during initial endoscopy (from the CODE BLUE-J Study). The assessed outcomes encompassed rebleeding and other clinical parameters. The rebleeding rates within 30 days in patients with blood group O and those without blood group O were 17.9% and 14.9%, respectively. Similarly, the rates within 1 year were 21.9% for patients with blood group O and 18.2% for those without blood group O. In a multivariate analysis using age, sex, vital signs at presentation, blood test findings, comorbidities, antithrombotic medication, active bleeding, and type of endoscopic treatment as covariates, patients with blood group O exhibited significantly higher risks for rebleeding within 30 days (odds ratio [OR] 1.31; 95% confidence interval [CI] 1.04–1.65; P = 0.024) and 1 year (OR 1.29; 95% CI 1.04–1.61; P = 0.020) compared to those without blood group O. However, the thrombosis and mortality rates did not differ significantly between blood group O and non-O patients. In patients with ALGIB, blood group O has been identified as an independent risk factor for both short- and long-term rebleeding.

Abstract The study aimed to identify prognostic factors for patients with acute lower gastrointestinal bleeding and to develop a high-accuracy prediction tool. The analysis included 8254 cases of acute hematochezia patients who were admitted urgently based on the judgment of emergency physicians or gastroenterology consultants (from the CODE BLUE J-study). Patients were randomly assigned to a derivation cohort and a validation cohort in a 2:1 ratio using a random number table. Assuming that factors present at the time of admission are involved in mortality within 30 days of admission, and adding management factors during hospitalization to the factors at the time of admission for mortality within 1 year, prognostic factors were established. Multivariate analysis was conducted, and scores were assigned to each factor using regression coefficients, summing these to measure the score. The newly created score (CACHEXIA score) became a tool capable of measuring both mortality within 30 days (ROC-AUC 0.93) and within 1 year (C-index, 0.88). The 1-year mortality rates for patients classified as low, medium, and high risk by the CACHEXIA score were 1.0%, 13.4%, and 54.3% respectively (all P

Abstract Background and Aim Helicobacter pylori eradication therapy effectively improves the abdominal symptoms and bowel habits of patients. Patients in whom dyspepsia is under control by 6 to 12 months after successful H. pylori eradication are defined as having H. pylori‐associated dyspepsia, and patients with dyspepsia that is refractory to successful eradication are defined as having functional dyspepsia. Here, we aimed to investigate the association between H. pylori eradication and improvement of dyspepsia in the short and long term after eradication therapy. Methods Dyspeptic symptoms before treatment and at 2 and 12 months after eradication were evaluated using the Gastrointestinal Symptom Rating Scale (GSRS) in 282 H. pylori‐positive Japanese patients who underwent eradication therapy. Results Of the Japanese H. pylori‐positive patients, 48.2% (136/282) had upper abdominal symptoms. Eradication improved dyspepsia in 34.5% (47/136) of the patients at 2 months post eradication, which continued to be under control up to 12 months. A significant decrease at 2 and 12 months after eradication, compared with before eradication, was observed in total GSRS (from 25.7 ± 10.4 [before eradication, n = 249] to 23.3 ± 7.2 [after 2 months, n = 249] and 24.8 ± 7.8 [after 12 months, n = 81]; P = 0.014 and 0.321, respectively), gastric pain score (from 4.1 ± 1.9 to 3.7 ± 1.3 and 3.7 ± 1.2; P = 0.025 and 0.047), and constipation score (from 5.9 ± 3.1 to 5.2 ± 2.3 and 5.9 ± 3.0; P

The prognosis of patients with advanced renal cell carcinoma (RCC) has improved with newer therapies, including molecular-targeted therapies and immuno-oncology agents. Despite these therapeutic advances, many patients with metastatic disease remain uncured. Inhibition of glycogen synthase kinase-3β (GSK-3β) is a promising new therapeutic strategy for RCC; however, the precise regulatory mechanism has not yet been fully elucidated. MicroRNAs (miRNAs) act as post-translational regulators of target genes, and we investigated the potential regulation of miRNAs on GSK-3β in RCC. We selected nine candidate miRNAs from three databases that could potentially regulate GSK-3β. Among these, hsa-miR-4465 (miR-4465) was downregulated in RCC cell lines and renal cancer tissues. Furthermore, luciferase assays revealed that miR-4465 directly interacted with the 3′ untranslated region of GSK-3β, and Western blot analysis showed that overexpression of miR-4465 significantly decreased GSK-3β protein expression. Functional assays showed that miR-4465 overexpression significantly suppressed cell invasion of A498 and Caki-1 cells; however, cell proliferation and migration were suppressed only in Caki-1 and A498 cells, respectively, with no effect on cell cycle and apoptosis. In conclusion, miR-4465 regulates GSK-3β expression but does not consistently affect RCC cell function as a single molecule. Further comprehensive investigation of regulatory networks is required in this field.

Abstract Background and Aim While short and long attachment caps are available for colonoscopy, it is unclear which type is more appropriate for stigmata of recent hemorrhage (SRH) identification in acute hematochezia. This study aimed to compare the performance of short versus long caps in acute hematochezia diagnoses and outcomes. Methods We selected 6460 patients who underwent colonoscopy with attachment caps from 10 342 acute hematochezia cases in the CODE BLUE‐J study. We performed propensity score matching (PSM) to balance baseline characteristics between short and long cap users. Then, the proportion of definitive or presumptive bleeding etiologies found on the initial colonoscopy and SRH identification rates were compared. We also evaluated rates of blood transfusions, interventional radiology, or surgery, as well as the rate of rebleeding and mortality within 30 days after the initial colonoscopy. Results A total of 3098 patients with acute hematochezia (1549 short cap and 1549 long cap users) were selected for PSM. The rate of colonic diverticular bleeding (CDB) diagnosis was significantly higher in long cap users (P = 0.006). While the two groups had similar rates of the other bleeding etiologies, the frequency of unknown etiologies was significantly lower in long cap users (P

Advanced bladder cancer (BC) (local invasive and/or metastatic) is not curable even with cytotoxic chemotherapy, immune checkpoint inhibitors, and targeted treatment. Targeting GSK-3β is a promising novel approach in advanced BC. The induction of autophagy is a mechanism of secondary resistance to various anticancer treatments. Our objectives are to investigate the synergistic effects of GSK-3β in combination with autophagy inhibitors to evade GSK-3β drug resistance. Small molecule GSK-3β inhibitors and GSK-3β knockdown using siRNA promote the expression of autophagy-related proteins. We further investigated that GSK-3β inhibition induced the nucleus translocation of transcription factor EB (TFEB). Compared to the GSK-3β inhibition alone, its combination with chloroquine (an autophagy inhibitor) significantly reduced BC cell growth. These results suggest that targeting autophagy potentiates GSK-3β inhibition-induced apoptosis and retarded proliferation in BC cells.

Abstract Immune checkpoint inhibitors (ICI) have dramatically changed the treatment of metastatic renal cell carcinoma (mRCC). Although many studies have reported biomarkers as predicting the efficacy of ICI in mRCC, they remain controversial and have challenges to apply in real-world practice. We evaluated prognostic significance of multiple molecules associated with tumor immunity in patients treated with ICI. The molecules were detected in tumor tissues by immunohistochemical staining. We identified CD8-positive T cells and CD68-positive macrophages infiltrating into the tumor tissue as significant favorable prognostic factors for ICI treatment. Conversely, high expression of CD4-positive T cells was associated with poor response to ICI. Furthermore, we demonstrated that scoring for the expression status of these three molecules provides a remarkably accurate biomarker in patients with mRCC. Even the classical approach of immunohistochemistry could predict the outcome of ICI treatment by assessing the combined status of tumor-infiltrating immune cells.

Abstract Outcomes of acute lower gastrointestinal bleeding have not been compared according to hospital capacity. We aimed to perform a propensity score-matched cohort study with path and mediation analyses for acute hematochezia patients. Hospitals were divided into high- versus low-volume hospitals for emergency medical services. Rebleeding and death within 30 days were compared. Computed tomography, early colonoscopy (colonoscopy performed within 24 h), and endoscopic therapies were included as mediators. A total of 2644 matched pairs were yielded. The rebleeding rate within 30 days was not significant between high- and low-volume hospitals (16% vs. 17%, P = 0.44). The mortality rate within 30 days was significantly higher in the high-volume cohort than in the low-volume cohort (1.7% vs. 0.8%, P = 0.003). Treatment at high-volume hospitals was not a significant factor for rebleeding (odds ratio [OR] = 0.91; 95% confidence interval [CI], 0.79–1.06; P = 0.23), but was significant for death within 30 days (OR = 2.03; 95% CI, 1.17–3.52; P = 0.012) on multivariate logistic regression after adjusting for patients’ characteristics. Mediation effects were not observed, except for rebleeding within 30 days in high-volume hospitals through early colonoscopy. However, the direct effect of high-volume hospitals on rebleeding was not significant. High-volume hospitals did not improve the outcomes of acute hematochezia patients.

Abstract Background Endoscopic removal of colorectal adenoma is considered an effective treatment for reducing the mortality rates associated with colorectal cancer. Warfarin, a type of anticoagulant, is widely used for the treatment and prevention of thromboembolism; however, bleeding may increase with its administration after polypectomy. In recent times, a high incidence of bleeding after endoscopic polypectomy has been reported in patients receiving heparin bridge therapy. However, previous studies have not compared the bleeding rate after endoscopic colorectal polypectomy between patients who continued with anticoagulant therapy and those who received heparin bridge therapy. We hypothesised that endoscopic colorectal polypectomy under the novel treatment with continuous warfarin is not inferior to endoscopic colorectal polypectomy under standard treatment with heparin bridge therapy with respect to the rate of postoperative bleeding. This study aims to compare the efficacy of endoscopic colorectal polypectomy with continuous warfarin administration and endoscopic colorectal polypectomy with heparin bridge therapy with respect to the rate of postoperative bleeding. Methods We will conduct a prospective multicentre randomised controlled non-inferiority trial of two parallel groups. We will compare patients scheduled to undergo colorectal polypectomy under anticoagulant therapy with warfarin. There will be 2 groups, namely, a standard treatment group (heparin bridge therapy) and the experimental treatment group (continued anticoagulant therapy). The primary outcome measure is the rate of postoperative bleeding. On the contrary, the secondary outcomes include the rate of cumulative bleeding, rate of overt haemorrhage (that does not qualify for the definition of haemorrhage after endoscopic polypectomy), incidence of haemorrhage requiring haemostasis during endoscopic polypectomy, intraoperative bleeding during endoscopic colorectal polypectomy requiring angiography, abdominal surgery and/or blood transfusion, total rate of bleeding, risk factors for postoperative bleeding, length of hospital stay, incidence of thromboembolism, prothrombin time-international ratio (PT-INR) 28 days after the surgery, and incidence of serious adverse events. Discussion The results of this randomised controlled trial will provide valuable information for the standardisation of management of anticoagulants in patients scheduled to undergo colorectal polypectomy. Trial registration UMIN-CTR UMIN000023720 . Registered on 22 August 2016

Background/Aims We retrospectively analyzed Crohn’s disease (CD) patients with small intestinal strictures who underwent single-balloon enteroscopy (SBE) to ascertain whether prototype SBEs with a passive bending mechanism and high force transmission insertion tube had better insertability in the small intestine than a conventional SBE. Methods Among 253 CD patients who underwent SBE, we identified 94 CD patients who had undergone attempted endoscopic balloon dilatation (EBD) for small intestinal stenosis for inclusion in this study. We analyzed whether the type of scope used for their initial procedure affected the cumulative surgery-free rate. For the insertability analysis, patients who underwent SBE at least twice were divided into 3 groups according to the type of scope used: conventional SBE only, prototype SBE only, and both conventional and prototype SBEs. For each group, depth of insertion, procedure time, and number of EBDs were compared in the same patient at different time points. Results The success rate of EBD was 88.3%. The 5- and 10-year cumulative surgery-free rate was 75.7% and 72.8%, respectively. Cox regression analysis indicated that the factors contributing to surgery were long stricture (≥2 cm), EBD failure, and elevated Crohn’s Disease Activity Index, but not the type of scope used for EBD. The prototype SBEs significantly improved the depth of insertion (P=0.03, Wilcoxon’s signed-rank test). Conclusions In CD patients with small intestinal stenosis, the prototype SBEs with a passive bending mechanism and high force transmission insertion tube did not improve long-term EBD outcome but did improve deep insertability. (Clinical Trial Registration No. UMIN000037102)

It remains unclear whether texture- and color-enhancement imaging (TXI) and narrow-band imaging (NBI) provide an advantage over white-light imaging (WLI) in Barrett’s esophagus. We compared endoscopic findings and color differences between WLI and image-enhanced endoscopy (IEE) using a third-generation ultrathin endoscope. We retrospectively enrolled 40 patients who evaluated Barrett’s esophagus using WLI, TXI, and NBI. Color differences determined using the International Commission on Illumination 1976 (L∗, a∗, b∗) color space among Barrett’s epithelium, esophageal, and gastric mucosa were compared among the endoscopic findings. As the secondary outcome, we assessed the subjective visibility score among three kinds of endoscopic findings. The prevalence of Barrett’s esophagus and gastroesophageal reflux disease (GERD) in WLI was 82.5% and 47.5%, respectively, and similar among WLI, TXI, and NBI. Color differences between Barrett’s epithelium and esophageal or gastric mucosa on NBI were significantly greater than on WLI (all p < 0.05). However, the color difference between Barrett’s epithelium and esophageal mucosa was significantly greater on NBI than TXI (p < 0.001), and the visibility score of Barrett’s epithelium detection was significantly greater on TXI than NBI (p = 0.022), and WLI (p = 0.016). High-vision, third-generation ultrathin endoscopy using NBI and TXI is useful for evaluating Barrett’s epithelium and GERD compared with WLI alone.

We report a case of sudden-onset pulmonary edema due to failure of a bioprosthetic mitral valve. Gross inspection revealed a leaflet tear at a stent post without calcification or pannus formation and no evidence of sutures. This case highlights the mechanical failure of a bioprosthetic mitral valve associated with missing sutures. (Level of Difficulty: Intermediate.)

Abstract Background There is no established treatment after failure of proven therapies for patients with metastatic renal cell carcinoma. Case presentation A 66-year-old Japanese man with metastatic renal cell carcinoma became refractory to interferon α and sunitinib therapies. He started treatment with axitinib at 10 mg/day, and the dose was gradually tapered down to 4 mg/day because of intolerable adverse events. His metastatic lesions shrank; however, he could not continue due to the adverse events. He started fourth-line therapy with nivolumab; however, the metastatic lesions increased. Rechallenge with axitinib 4 mg/day was started, and the dose was reduced to 2 mg/day because of adverse events. Subsequently, the adverse events became controllable, and the metastatic lesions were maintained at reduced size. Conclusion Therapeutic drug monitoring of axitinib could play an important role in the development of safe and effective therapeutic treatment and individualization of these medications.

Background/Aims There are few prospective studies on cold forceps polypectomy (CFP) using jumbo cup forceps. Therefore, we examined patients with diminutive polyps (5 mm or smaller) treated with CFP using jumbo cup forceps to achieve an adenoma-free colon and also assessed the safety of the procedure and the recurrence rate of missed or residual polyp after CFP by performing follow-up colonoscopy 1 year later. Methods We included patients with up to 5 adenomas removed at initial colonoscopy and analyzed data from a total of 361 patients with 573 adenomas. One-year follow-up colonoscopy was performed in 165 patients, at which 251 lesions were confirmed. Results The one-bite resection rate with CFP was highest for lesions 3 mm or smaller and decreased significantly with increasing lesion size. Post-procedural hemorrhage was observed in 1 of 573 lesions (0.17%). No perforation was noted. The definite recurrence rate was 0.8% (2/251 lesions). The probable recurrence rate, which was defined as recurrence in the same colorectal segment, was 17%. Adenoma-free colon was achieved in 55% of patients at initial resection. Multivariate analysis revealed that achievement of an adenoma-free colon was significantly associated with number of adenomas and years of endoscopic experience. Conclusions CFP using jumbo biopsy forceps was safe and showed a high one-bite resection rate for diminutive lesions of 3 mm or smaller. The low definite recurrence rate confirms the reliability of CFP using jumbo biopsy forceps. Number of adenomas and years of endoscopic experience were key factors in achieving an adenoma-free colon.

A 67-year-old man was diagnosed with non-muscle invasive bladder cancer and underwent transurethral resection of the lesions in August 2017. The pathological findings revealed high-grade urothelial carcinoma. The tumor relapsed as urothelial carcinoma with sarcomatoid/osteosarcoma variant with vascular invasion, and transurethral resection was performed in December 2017. He underwent laparoscopic radical cystoprostatectomy and orthotopic neobladder reconstruction using ileum in March 2018. The patient developed lung metastasis in July 2018. He underwent four courses of chemotherapy with doxorubicin and thoracoscopic left lower lobectomy of the lung in October 2018.

Myeloid sarcoma is an extramedullary tumor composed of immature myeloid cells and occurs in various extramedullary sites. We report a 48-year-old man diagnosed with myeloid sarcoma in the epididymis. He was admitted to our hospital due to a painless right intrascrotal mass. Magnetic resonance imaging showed a 30 mm tumor in the right epididymis, and we subsequently performed right high orchiectomy. The pathological diagnosis was myeloid sarcoma. Bone marrow aspiration and biopsy revealed no hematological disease, and cytogenetic analysis in the bone marrow showed normal karyotype. He was diagnosed with isolated myeloid sarcoma in the epididymis. Six months after the operation, myeloid sarcoma recurred in the para aorta and left sub-diaphragm. Bone marrow examination revealed myelodysplastic syndrome, and cytogenetic analysis showed 46, XY. We performed surgical resection of the recurrent mass, and cytogenetic analysis showed 47, XY, +21. He was diagnosed with recurrent MS with adult-onset trisomy 21. Although the effect of trisomy 21 on prognosis is unknown, the patient is currently undergoing systemic chemotherapy with maintained remission.

Cervical adenocarcinomas are believed to lose estrogen response on the basis of no expression of a nuclear estrogen receptor such as ERα in clinical pathology. Here, we demonstrated that cervical adenocarcinoma cells respond to a physiological concentration of estrogen to upregulate claudin-1, a cell surface molecule highly expressed in cervical adenocarcinomas. Knockout of claudin-1 induced apoptosis and significantly inhibited proliferation, migration, and invasion of cervical adenocarcinoma cells and tumorigenicity in vivo. Importantly, all of the cervical adenocarcinoma cell lines examined expressed a membrane-bound type estrogen receptor, G protein–coupled receptor 30 (GPR30/GPER1), but not ERα. Estrogen-dependent induction of claudin-1 expression was mediated by GPR30 via ERK and/or Akt signaling. In surgical specimens, there was a positive correlation between claudin-1 expression and GPR30 expression. Double high expression of claudin-1 and GPR30 predicts poor prognosis in patients with cervical adenocarcinomas. Mechanism-based targeting of estrogen/GPR30 signaling and claudin-1 may be effective for cervical adenocarcinoma therapy.

Nuchal-type fibroma is a rare benign fibrous tumor that is mainly located in the nuchal region. However, about one-third of the tumors occur in the extranuchal region. This tumor has specific histopathologic findings; it is composed of dense paucicellular, sclerotic, thick and haphazardly arranged collagen fibers. We report a 58-year-old man who presented with perineal nuchal-type fibroma originating in the perirectal region. This tumor was surgically excised; however, the fibrous band from tumor reached into levator ani muscle and was resected incompletely. Continuous follow up is needed even though this tumor is benign. Keywords: Nuchal-type fibroma, Perineum, Peri-rectum

We report a 70-year-old woman diagnosed with unicentric Castleman’s disease with a contrast well-enhanced retroperitoneal tumor of 25 mm in diameter that located between the aorta and inferior vena cava. The imaging finding did not suggest any specific features, and no other lesion was detected. Laboratory examinations indicating malignant lymphoma such as soluble interleukin-2 were all negative. We resected the retroperitoneal tumor laparoscopically, and histopathological examination revealed hyaline vascular type Castleman’s disease. Although complete resection of hyaline vascular type unicentric Castleman’s disease results in a good prognosis, a late relapse has been reported and long-term follow-up is warranted.

A 44-year-old woman visited a hospital with microscopic hematuria in June 2009. Computed tomography showed a large bladder diverticulum at right lateral wall and urachal remnant. Cystoscopic examination showed a large diverticulum at the right lateral wall that closes to the dome. She was followed up closely without therapeutic intervention; however, the residual urine increased gradually and frequent bladder diverticulitis developed. She underwent laparoscopic bladder diverticulectomy and excision of the urachal remnant simultaneously without any complications in August 2017. Laparoscopic approach for a large bladder diverticulum and urachal remnant is useful with safe, effective, and minimally invasive.

Background: Helicobacter pylori eradication containing the potassium-competitive acid blocker, vonoprazan, achieves a higher eradication rate than therapy with proton pump inhibitors (PPIs). Because vonoprazan is mainly metabolized by CYP3A4/5, CYP genotype may affect the eradication rate. We investigated the influence of antibiotic susceptibility and CYP3A4/5 and CYP2C19 genotypes on the eradication rates. Methods: A total of 307 Japanese who were genotyped for CYP3A4 *1/*22, CYP3A5 *1/*3 and CYP2C19 *1/*2/*3/*17, and investigated for susceptibility to antimicrobial agents, received vonoprazan-containing regimens: (1) With amoxicillin and clarithromycin as the first-line treatment; (2) with amoxicillin and metronidazole as the second-line treatment; or (3) with amoxicillin and sitafloxacin as the third-line treatment. Results: The eradication rate was 84.5% (95% confidence interval [CI]: 78.9–89.1%) using first-line, 92.6% (95% CI: 82.1–97.9%) using second-line and 87.5% (95% CI: 73.1–95.8%) using third-line treatment. Infection with clarithromycin-resistant strains was a predictive factor for failed eradication (odds ratio: 5.788, 95% CI: 1.916–17.485, p = 0.002) in multivariate analysis. No significant differences were observed in the eradication rate of regimens among CYP3A4, CYP3A5 and CYP2C19 genotypes. Conclusions: Genotyping for CYP3A4 *1/*22, CYP3A5 *1/*3 and CYP2C19 *1/*2/*3/*17 before vonoprazan-containing eradication treatment may not be useful for predicting clinical outcomes.

Prognostic factors and therapeutic targets are needed for the patients with cervical adenocarcinoma because they have a poor prognosis. Recently, co-expression of multiple receptor tyrosine kinases (RTKs) has been found to be associated with aggressive biological behavior and poor prognosis of several types of malignancy. To evaluate the significance of the expression of multiple RTKs in uterine cervical cancers, we examined the expression profile of RTKs (EGFR, HER2 and c-Met) and the correlation of their expression with clinicopathological features and prognosis of patients with cervical adenocarcinomas. AIS and adenocarcinoma showed strong expression of a single RTK (EGFR, HER2 or c-Met) on the cell membrane in 41 (77.4%) of 53 cases. Twenty (46%) of the 43 adenocarcinoma cases were positive for double or triple RTKs (P = 0.034). Positivity for EGFR and double positivity for EGFR and HER2 (EGFR+/HER2+/c-Met+ and EGFR+/HER2+/c-Met-) were significantly correlated with lymph node metastasis (P = 0.010 for single and P = 0.013 for double) and UICC stage (P = 0.021 for single and P = 0.007 for double). Positivity for HER2 was significantly correlated with tumor size (P = 0.029). Relapse-free survival (RFS) was significantly shorter in patients who were double positive for EGFR and HER2. Our results suggest that EGFR and HER2 are potential therapeutic targets and that their co-expression is a prognostic factor for cervical adenocarcinoma.

The failure of normal hematopoiesis is observed in myeloid neoplasms. However, the precise mechanisms governing the replacement of normal hematopoietic stem cells in their niche by myeloid neoplasm stem cells have not yet been clarified. Primary acute myeloid leukemia and myelodysplastic syndrome cells induced aberrant expression of multiple hematopoietic factors including Jagged-1, stem cell factor and angiopoietin-1 in mesenchymal stem cells even in non-contact conditions, and this abnormality was reverted by extracellular vesicle inhibition. Importantly, the transfer of myeloid neoplasm-derived extracellular vesicles reduced the hematopoietic supportive capacity of mesenchymal stem cells. Analysis of extracellular vesicle microRNA indicated that several species, including miR-7977 from acute myeloid leukemia cells, were higher than those from normal CD34+ cells. Remarkably, the copy number of miR-7977 in bone marrow interstitial fluid was elevated not only in acute myeloid leukemia, but also in myelodysplastic syndrome, as compared with lymphoma without bone marrow localization. The transfection of the miR-7977 mimic reduced the expression of the posttranscriptional regulator, poly(rC) binding protein 1, in mesenchymal stem cells. Moreover, the miR-7977 mimic induced aberrant reduction of hematopoietic growth factors in mesenchymal stem cells, resulting in decreased hematopoietic-supporting capacity of bone marrow CD34+ cells. Furthermore, the reduction of hematopoietic growth factors including Jagged-1, stem cell factor and angiopoietin-1 were reverted by target protection of poly(rC) binding protein 1, suggesting that poly(rC) binding protein 1 could be involved in the stabilization of several growth factors. Thus, miR-7977 in extracellular vesicles may be a critical factor that induces failure of normal hematopoiesis via poly(rC) binding protein 1 suppression.

Two thioacetyl-terminated ferrocene-anthraquinone donor-acceptor molecules with different π-electron conjugative units have been synthesized via a series of Stille and Sonagashira reactions. Their photochemical and electrochemical properties before and after addition of an organic acid are investigated, indicating that these complexes are sensitive to external perturbation of protonation, leading the structural change to an expansion of π-conjugated system by cyclocondensation reaction and promoting intramolecular electron transfer from donor to acceptor. They would be good candidates for studies of novel SAMs, and the properties triggered by protonation-induced intramolecular electron transfer will make the SAMs be useful in designing new functional molecular devices.

The human nasal epithelium is the first line of defense during respiratory virus infection. Respiratory syncytial virus (RSV) is the major cause of bronchitis, asthma and severe lower respiratory tract disease in infants and young children. We previously reported in human nasal epithelial cells (HNECs), the replication and budding of RSV and the epithelial responses, including release of proinflammatory cytokines and enhancement of the tight junctions, are in part regulated via an NF-κB pathway. In this study, we investigated the effects of the NF-κB in HNECs infected with RSV. Curcumin prevented the replication and budding of RSV and the epithelial responses to it without cytotoxicity. Furthermore, the upregulation of the epithelial barrier function caused by infection with RSV was enhanced by curcumin. Curcumin also has wide pharmacokinetic effects as an inhibitor of NF-κB, eIF-2α dephosphorylation, proteasome and COX2. RSV-infected HNECs were treated with the eIF-2α dephosphorylation blocker salubrinal and the proteasome inhibitor MG132, and inhibitors of COX1 and COX2. Treatment with salubrinal, MG132 and COX2 inhibitor, like curcumin, prevented the replication of RSV and the epithelial responses, and treatment with salubrinal and MG132 enhanced the upregulation of tight junction molecules induced by infection with RSV. These results suggest that curcumin can prevent the replication of RSV and the epithelial responses to it without cytotoxicity and may act as therapy for severe lower respiratory tract disease in infants and young children caused by RSV infection.