Effect of sofosbuvir and velpatasvir therapy on clinical outcome in hepatitis C virus patients with decompensated cirrhosis.

AIM: To determine the impact of direct-acting antiviral therapy on the long-term prognosis of decompensated cirrhotic patients. METHODS: A total of 37 patients with hepatitis C virus-induced decompensated cirrhosis treated with sofosbuvir and velpatasvir (SOF/VEL group) were prospectively enrolled. For historical control, 65 hepatitis C virus-positive decompensated cirrhotic patients who did not receive direct-acting antiviral therapy were included (control group). The incidence rates of hepatocellular carcinoma (HCC), decompensated events with hospitalization, and overall survival were compared between both groups. RESULTS: A total of 41 patients experienced decompensated events during 15.0 months in the control group, and six patients during 21.6 months in the SOF/VEL group. The cumulative incidence rates of decompensated events after 2 years were significantly higher in the control group (53.1%) than in the SOF/VEL group (14.5%; p < 0.001). A total of 27 patients died within 22.0 months in the control group, and three patients died within 25.6 months in the SOF/VEL group. The overall survival rates after 2 years were significantly lower in the control group (67.6%) than in the SOF/VEL group (91.3%; p = 0.010). A total of 13 patients in the control group developed HCC during 15.8 months, and 10 patients during 17.3 months in the SOF/VEL group. The HCC incidence rates after 2 years were 20.3% and 29.6% in the control and SOF/VEL groups, respectively, with no significant difference (p = 0.327). CONCLUSIONS: SOF/VEL therapy may suppress the development of decompensated events and improve the prognosis in decompensated cirrhotic patients; however, the incidence of HCC remains prevalent in these patients irrespective of SOF/VEL therapy.

Experimental development of a gated UV-induced spectroscopic lidar for the daytime study of plant ecology and photosynthesis: multi-modal measurement of fluorescence of trees growing in a field and Mie-Raman-fluorescence of the surrounding atmosphere.

A gated UV-induced spectroscopic lidar operational during daylight was developed to better understand the plant growth status in real time and the influence from the surrounding atmosphere chemical environment. Initial indoor experiments and short-range (100 m) field measurements were very positive. The lidar worked as a vegetation fluorescence lidar, as well as an atmospheric Mie-Raman-fluorescence lidar. A UV (355 nm) laser was effective to induce fluorescence and Raman scattering, and a synchronous detection technique made it possible to detect weak signals, even in daytime. Tree spectra containing chlorophyll fluorescence of tree leaves offered information about the growth status of trees. Atmospheric spectra containing aerosol Mie scattering, N 2, O 2, H 2 O Raman scattering, and pollutant fluorescence helped us to learn about atmospheric circumstances surrounding trees. The multi-modal information is useful for comprehensive understanding of plant ecology.

Comparison of atezolizumab plus bevacizumab and lenvatinib in terms of efficacy and safety as primary systemic chemotherapy for hepatocellular carcinoma.

AIM: Atezolizumab plus bevacizumab and lenvatinib have each shown efficacy as primary systemic chemotherapies for hepatocellular carcinoma (HCC) in clinical trials. However, comparative trials of these two treatments have not been conducted. This study aimed to compare the therapeutic outcomes of these two treatments. METHODS: This prospectively registered multicenter study analyzed 272 patients with HCC who received atezolizumab plus bevacizumab (the Atezo + Beva group; n = 90) or lenvatinib (the Len group; n = 182) as primary systemic chemotherapy. After propensity score matching (PSM), 66 patients were assigned to each group. RESULTS: After PSM, the median progression-free survival (PFS) was significantly longer in the Atezo + Beva group than in the Len group (8.8 vs. 5.2 months; p = 0.012). No significant differences were noted between the two groups in terms of median overall survival (not reached vs. 20.6 months; p = 0.577), objective response rates (43.8% vs. 52.4%; p = 0.330), and disease control rates (76.6% vs. 82.5%; p = 0.404). The percentage of patients with modified albumin-bilirubin grades of one or 2a was maintained during treatment in the Atezo + Beva group but decreased over time in the Len group. The rate of discontinuation due to adverse events (AEs) was lower in the Atezo + Beva group than in the Len group (12.1% vs. 28.8%; p = 0.018). CONCLUSIONS: Atezolizumab plus bevacizumab showed prolonged PFS, maintained hepatic reserve, and had lower rates of severe AEs compared with that on using lenvatinib as primary systemic chemotherapy for HCC.

Candidemia in patients with head and neck cancer: mortality and a novel risk factor.

PURPOSE: Candidemia is a bloodstream infection (BSI) by Candida spp. and is associated with high mortality. However, there have been few reports about BSI in head and neck cancer (HNC). We aimed to evaluate the impact of candidemia in patients with HNC and compared it with bacteremia. STUDY DESIGN: A multicenter retrospective study. METHODS: We retrospectively analyzed 83 BSI episodes in HNC (2011 to 2020) and divided them into the candidemia and bacteremia groups. We then compared the survival rate and risk factors for candidemia between the groups. RESULTS: The overall cumulative incidence (risk) of candidemia in BSI was 12 out of 83 episodes (14.5%). The 1-year mortality for the bacteremia and candidemia groups was 33.3% and 58.3%, respectively (log-rank p = 0.041). Broad-spectrum antibiotics (odds ratio [OR]: 29.5; 95% confidence interval [CI], 2.49-350), mucositis (OR 11.0; 95% CI, 1.52-80.1), and malignant wounds (OR 79.5; 95% CI 1.33-4737) were significant risk factors for candidemia in HNC. CONCLUSIONS: Candidemia causes high mortality in patients with HNC. To our knowledge, malignant wounds have not been previously reported as a risk factor for candidemia. For early diagnosis and treatment of candidemia, risk factors should be considered, and antifungal therapy started earlier.

Efficacy and safety of cold forceps biopsy for diminutive pharyngeal neoplasms: Single-center, prospective pilot study.

BACKGROUND: Management of diminutive pharyngeal neoplasms is controversial. Thus, we conducted a single-center, prospective pilot study to investigate the efficacy and safety of endoscopic excision with cold forceps biopsy (CFB) of these lesions. PATIENTS AND METHODS: Thirty-nine lesions endoscopically diagnosed with narrow-band imaging as pharyngeal neoplasms of 3 mm or smaller were excised with CFB using jumbo biopsy forceps (cap diameter 2.8 mm, jaw volume 12.4 mm3 ). The primary outcome was endoscopically determined local remnant/recurrence rate 3 months after CFB. The secondary outcomes were histopathologically determined local remnant/recurrence rate; risk factors associated with the endoscopic remnant/recurrence; and incidence of intraoperative or delayed bleeding and other adverse events. RESULTS: Histological diagnosis of the 39 CFB-excised lesions were: 11 high-grade dysplasia (28.2%), 22 low-grade dysplasia (56.4%), two basal cell hyperplasia (5.1%) and four atypical squamous epithelium (10.3%).Twenty-seven patients (30 lesions) underwent follow-up endoscopy 3 months after CFB; the endoscopic and pathological local remnant/recurrence rate was 20% (6/30; 95% confidence interval (CI), 7.7-36.6%) and 16.7% (5/30; 95% CI, 5.6-34.7%), respectively. Location of the lesion in the hypopharynx was a significant risk factor associated with the endoscopic local remnant/recurrence (P = 0.049). No significant adverse events occurred. CONCLUSIONS: Cold forceps biopsy with jumbo biopsy forceps appears to be a safe and effective technique for excising diminutive pharyngeal neoplasms. Although small, the excised lesions may have a remarkably high frequency of high-grade dysplasia. (Clinical trial registration number: UMIN000037980).

[Nivolumab‒Induced Severe Thrombocytopenia in a Patient with Advanced Gastric Cancer].

Here, we report a case of severe thrombocytopenia induced by nivolumab. A 70‒year‒old woman with advanced gastric cancer was treated with nivolumab. After the first dose, she noticed an erythematous rash. During the second cycle, fever and purpura on the lower extremities were also noted. Laboratory examinations revealed severe thrombocytopenia of grade 4, mild hemolytic anemia, leukopenia, and coagulopathy. Immune‒related adverse events(irAE)were suspected, and we started 40 mg(0.7 mg/kg)prednisolone(PSL)per day. Her symptoms and laboratory data immediately improved. However, when we reduced the dose of PSL, she developed rash and thrombocytopenia again. We increased the dose of PSL to 40 mg, which was effective for improving these abnormalities. We then gradually reduced the PSL, paying attention to avoid a relapse of irAEs. We could not restart chemotherapy thereafter, and she died from progression of gastric cancer. As shown in this case, PSL is effective for immune‒related thrombocytopenia; however, determining how to reduce the dose of PSL and when to restart chemotherapy requires careful consideration.

Effect of Vonoprazan on Delayed Bleeding after Endoscopic Submucosal Dissection for Gastric Neoplasia among Antithrombotic Drug Users: A Single-Center, Single-Arm Prospective Observational Case Control Study.

Antithrombotic therapy is a major risk factor for delayed bleeding after endoscopic submucosal dissection (ESD) for gastric neoplasia. A potassium-competitive acid blocker, vonoprazan, is expected to prevent delayed bleeding better than conventional proton pomp inhibitors (PPIs), but the evidence is controversial. We sought to clarify the efficacy of vonoprazan for prevention of delayed bleeding after gastric ESD in patients under antithrombotic therapy. We prospectively registered 50 patients who underwent gastric ESD while receiving antithrombotic therapy and vonoprazan in our institution between October 2017 and September 2018. The incidence of delayed bleeding was compared with that in a historical control group of 116 patients treated with conventional PPI. We also evaluated risk factors associated with delayed bleeding. Delayed bleeding was observed in 8 of 50 patients (16.0%), which was not dissimilar from the incidence in the historical control group (12.1%) (p=0.49). In the univariate analysis, age (> 70 years) (p=0.034), multiple antithrombotic drug use (p<0.01), procedure time (> 200 min) (p=0.038) and tumor size (> 40 mm) (p<0.01) were associated with delayed bleeding after gastric ESD, but vonoprazan was not (p=0.49). Vonoprazan may not be more effective than conventional PPIs in preventing delayed bleeding after gastric ESD in patients receiving antithrombotic therapy.

The relationship between peripheral neuropathy and efficacy in second-line chemotherapy for unresectable advanced gastric cancer: a prospective observational multicenter study protocol (IVY).

BACKGROUND: Paclitaxel is used in second-line conventional chemotherapies to manage patients with unresectable advanced gastric cancer (GC). Paclitaxel-induced peripheral neuropathy is a known adverse event leading to treatment discontinuation. Additionally, oxaliplatin which causes irreversible peripheral neuropathy is now commonly used in first-line chemotherapy for advanced GC in Japan. Thus, examining the incidence of peripheral neuropathy with paclitaxel after oxaliplatin is necessary to improve the quality of life and outcomes of patients with advanced GC in the second-line treatment setting. METHODS: This prospective observational multicenter study, (which we named IVY study), will evaluate the degree of chemotherapy-induced peripheral neuropathy (CIPN) and the efficacy of second-line chemotherapy for unresectable advanced GC. A patient neurotoxicity questionnaire (PNQ) and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) will be used to assess CIPN during the second-line treatment. The key eligibility criteria are as follows: 1) unresectable or recurrent GC histologically confirmed to be primary adenocarcinoma of the stomach, 2) age over 20 years, 3) Eastern Cooperative Oncology Group performance status score of 0-2, 4) written informed consent following full study information is provided to the patient, 5) progression or intolerance for first-line chemotherapy comprising fluorinated pyrimidine and platinum anticancer drugs (cisplatin or oxaliplatin) for advanced GC. 6) presence of evaluable lesions as confirmed using a computed tomography (CT) or magnetic resonance imaging. A total of 200 patients is considered to be appropriate for inclusion in this study. DISCUSSION: The results of this study will provide some information on CIPN with the sequential usage of oxaliplatin as first-line chemotherapy to paclitaxel as second-line chemotherapy in clinical practice. TRIAL REGISTRATION: This trial is registered in the University Hospital Medical Information Network's Clinical Trials Registry with the registration number UMIN000033376 (Registered 11 July 2018).

Post-polypectomy bleeding in hot-snare polypectomy of colonic polyps under continued warfarin or short interruption of direct oral anticoagulants.

BACKGROUND: Newly published guidelines of the Japanese Gastroenterological Endoscopy Society (JGES) suggest to consider endoscopic procedures with high risk of bleeding without stopping warfarin and with stopping direct oral anticoagulants (DOACs) only on the day of the procedure. In this study, we aimed to test the validity of these recommendations. PATIENTS AND METHODS: We retrospectively reviewed medical records of 344 patients with anticoagulant therapy who underwent hot-snare polypectomy between January 2012 and October 2018. Patients (n = 132) with interruption of anticoagulants (3-7 days for warfarin and 2-3 days for DOACs before the procedure) and without heparin-bridging were excluded. Among the remaining 212 patients, the incidence of post-polypectomy bleeding was compared between the following 2 patient groups: patients who had interruption of anticoagulants with heparin-bridging (HB group, n = 139) and patients treated according to the new JGES guideline (FG group, n = 73). RESULTS: The rate of post-polypectomy bleeding (PPB) in FG group (9.6%) was not significantly different from that in HB group (12.9%, p = 0.5). In subgroup analysis, the incidence of bleeding in patients with warfarin (12.2%) and with DOAC (6.3%) in FG group was not significantly different from corresponding figures in HB group (14.2%, 0%). In multivariate analysis, number of resected polyps was associated with PPB, but the administration of anticoagulants according to the new guidelines was not a significant risk factor for PPB (p = .98). CONCLUSIONS: Our study affirms the recommendations of JGES for the management of anticoagulants in patients who undergo colonic polypectomy regarding post-polypectomy bleeding.

[Sclerosing mesenteritis diagnosed using computed tomography- and ultrasound-guided needle biopsy -utility of the coaxial technique].

Here, we report the case of an 82-year-old woman with sclerosing mesenteritis diagnosed using needle biopsy under the guidance of computed tomography (CT) and ultrasound (US). The patient manifested appetite loss, weight loss, and epigastric pain. CT of the abdomen and pelvis revealed increased density of the mesentery adjacent to the small bowel along with enlarged lymph nodes. Hence, we suspected sclerosing mesenteritis but also considered malignancies, such as lymphoma. We then performed CT- and US-guided needle biopsy with coaxial technique. We inserted an introducer needle by verifying its location using CT and extracted multiple specimens using a finer needle that passed through the introducer without incident. The collected specimens were adequate and histological diagnosis revealed sclerosing mesenteritis. We treated the patient with corticosteroids, and her symptoms and radiographic findings improved. Thus, the coaxial technique was a useful and minimally invasive tool for the diagnosis of sclerosing mesenteritis.

Risk factors for recurrent bleeding from acute hemorrhagic rectal ulcer.

OBJECTIVES: Acute hemorrhagic rectal ulcer (AHRU) occurs suddenly with painless massive bleeding from rectal ulcers, usually in patients who have severe underlying disorders. The rate of recurrent bleeding from AHRU is high, but there have been few studies on the risk factors for recurrent bleeding. The aim of this study was to identify risk factors for recurrent bleeding from AHRU. METHODS: Among 27,151 patients who underwent colonoscopy from 2006 November to 2017 March in our hospital, 120 patients with AHRU were retrospectively reviewed to identify risk factors for recurrent bleeding. Factors analyzed were: age, sex, Charlson Comorbidity Index (CCI), comorbidities (congestive heart failure, liver cirrhosis, renal failure, respiratory failure, diabetes mellitus and malignancy), medications (antiplatelet drugs, anticoagulants and steroids); endoscopic therapy and endoscopic features of AHRU. RESULTS: Recurrent bleeding from AHRU occurred in 30% of patients (36/120). In multi-variate analysis, individual comorbidities, medications, endoscopic features and endoscopic hemostasis were not significant or independent risk factors for recurrent bleeding. However, a high CCI score (4 or more) was a risk factor (odds ratio, 7.0; 95% confidence interval, 1.8-27.1). Endoscopic hemostasis was performed in 61% (73/120) of AHRU patients, and successful hemostasis was achieved in 99% of the treated patients (72/73). CONCLUSIONS: High CCI score was a predictor of recurrent bleeding from AHRU, but individual comorbidities, medications, endoscopic features or endoscopic hemostasis were not. Endoscopic hemostasis for bleeding from AHRU was achieved in most patients, but the recurrent bleeding rate was high.

Safety of cold polypectomy for small colorectal neoplastic lesions: a prospective cohort study in Japan.

BACKGROUND: Cold polypectomy has been widely accepted for removal of small colorectal polyps. However, no large-scale prospective study exists as for its safety in Japan. We investigated this issue in this single-center, prospective cohort study in a total of 1198 colorectal polyps resected with cold polypectomy. PATIENTS AND METHODS: Four hundred and seventy-four patients who underwent cold polypectomy for colorectal neoplastic lesions less than 10-mm diameter between September 2014 and October 2016 were enrolled. Primary outcome was the incidence of delayed bleeding within 2 weeks after the procedure. Secondary outcomes were the rate of immediate bleeding, perforation, endoscopic en bloc resection, and advanced histology. RESULTS: Cold polypectomy was performed on 1198 polyps in the 474 patients. No delayed bleeding or colonic perforation was observed. Immediate bleeding during the procedure, requiring endoscopic hemostasis, occurred in 97 lesions (8.1%), and all of them were successfully managed endoscopically. The endoscopic en bloc resection rate was 97.2%. Twenty-eight lesions (2.3%) were histologically diagnosed as advanced neoplasia; among them, three lesions were well-differentiated adenocarcinomas, and in two of them, a negative margin was not histologically confirmed. CONCLUSIONS: Cold polypectomy for small colorectal polyps is a safe technique without significant complication, but careful endoscopic diagnosis at cold polypectomy is necessary to identify advanced neoplasia. The reliability of cold polypectomy in excision of polyps with high-grade neoplasia should be established before the procedure becomes standard in the excision of small colorectal polyps. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000014812.

Frequency of, and factors associated with, hepatitis B virus reactivation in hepatitis C patients treated with all-oral direct-acting antivirals: Analysis of a Japanese prospective cohort.

AIM: Several case reports have shown that hepatitis B virus (HBV) reactivation developed in hepatitis C patients with a current or previous HBV infection during direct-acting antiviral (DAA) treatment, which led to severe hepatitis or death in some cases. However, its precise frequency and risk factors are not entirely clear. We analyzed a prospective cohort. METHODS: We analyzed HBV reactivation in 461 consecutive hepatitis C patients who received 12 weeks of ledipasvir/sofosbuvir for genotype 1 or sofosbuvir plus ribavirin for genotype 2 at multiple centers. RESULTS: By the examination of the preserved sera at baseline, 159 patients (34%) were identified as seropositive for HBV core antibody (anti-HBc) and were included in the subsequent analysis; 4 patients were positive for HBV surface antigen (HBsAg), and the others were negative. Serum HBV DNA was undetectable or was detectable but <20 IU/mL at baseline for all patients. Serial measurement of HBV DNA at 4 weeks and 12 weeks in the preserved serum samples was available in 147 patients and identified HBV reactivation (defined as the appearance of serum HBV DNA ≥20 IU/mL) in 2 HBsAg-positive and 3 HBsAg-negative patients. No patient developed HBV-associated hepatitis. Patients who developed HBV reactivation had significantly lower anti-HBs titers and higher serum alanine transferase levels before treatment. CONCLUSION: Hepatitis B virus reactivation during direct-acting antiviral therapies occurs in 3.4% (5/147) of patients who are positive for anti-HBc. A low titer of anti-HBs and a high serum alanine transferase level prior to treatment are associated with reactivation in this patient group.

Two cases of acute gastric dilation after radiofrequency catheter ablation for supraventricular arrhythmia.

We describe our experience with two cases of acute gastric dilation after radiofrequency catheter ablation (RFCA) for supraventricular arrhythmia. After the RFCA procedure, patients experienced epigastric pain, abdominal distension, and vomiting. Computed tomography showed marked dilation of their stomachs, but without apparent obstruction of the gastric antrum or the duodenum. Esophagogastroduodenoscopy and upper gastrointestinal series revealed significant gastroparesis. We considered that gastric hypomotility had been induced by vagus nerve injury after RFCA. Peristaltic stimulants effectively improved the patients' symptoms by improving gastric motility. There have been few reports of acute gastric dilation after RFCA in Japan to date, but the possibility of encountering this condition is expected to increase in parallel with the recent increased use of RFCA. Therefore, gastroenterologists should be alert to this rare complication.

Geranylgeranyltransferase Cwg2-Rho4/Rho5 module is implicated in the Pmk1 MAP kinase-mediated cell wall integrity pathway in fission yeast.

Pmk1, a fission yeast homologue of mammalian ERK MAPK, regulates cell wall integrity, cytokinesis, RNA granule formation and ion homeostasis. Our screen for vic (viable in the presence of immunosuppressant and chloride ion) mutants identified regulators of the Pmk1 MAPK signaling, including Cpp1 and Rho2, based on the genetic interaction between calcineurin and Pmk1 MAPK. Here, we identified the vic2-1 mutants carrying a mis-sense mutation in the cwg2(+) gene encoding a beta subunit of geranylgeranyltransferase I (GGTase I), which participates in the post-translational C-terminal modification of several small GTPases, allowing their targeting to the membrane. Analysis of the vic2-1/cwg2-v2 mutant strain showed that the localization of Rho1, Rho4, Rho5 and Cdc42, both at the plasma and vacuolar membranes, was impaired in the vic2-1/cwg2-v2 mutant cells. In addition, Rho4 and Rho5 deletion cells exhibited the vic phenotype and cell wall integrity defects, shared phenotypes among the components of the Pmk1 MAPK pathway. Consistently, the phosphorylation of Pmk1 MAPK on heat shock was decreased in the cwg2-v2 mutants, and rho4- and rho5-null cells. Moreover, Rho4 and Rho5 associate with Pck1/Pck2. Possible roles of Cwg2, Rho4 and Rho5 in the Pmk1 signaling will be discussed.

Spatial control of calcineurin in response to heat shock in fission yeast.

In fission yeast, Ppb1, the Ca2+/calmodulin-dependent protein phosphatase calcineurin regulates multiple biological processes, such as cytokinesis, Ca2+-homeostasis, membrane trafficking and cell wall integrity. Calcineurin dephosphorylates the Prz1 transcription factor, leading to its nuclear translocation and gene expression under the control of CDRE (calcineurin-dependent response element). Although the calcineurin-mediated spatial control of downstream transcription factors has been intensively studied in many organisms, less is known about the spatial regulation of calcineurin on stresses. Here, we show that heat shock stimulates calcineurin-dependent nuclear translocation of Prz1 and CDRE-dependent gene expression. Notably, calcineurin exhibited a dramatic change in subcellular localization, translocating from diffuse cytoplasmic to dot-like structures on heat shock. The calcineurin dots colocalized with Dcp2 or Pabp, the constituent of P-bodies or stress granules, respectively, thus suggesting that calcineurin is a component of RNA granules under heat shock. Importantly, the calcineurin inhibitor FK506 markedly inhibited the accumulation of calcineurin granules, whereas the constitutively active calcineurin strongly accumulated in the granules on heat shock, suggesting that phosphatase activity is important for calcineurin localization. Notably, the depletion of calcineurin induced a rapid appearance of Nrd1- and Pabp-positive RNA granules. The possible roles of calcineurin in response to heat shock will be discussed.

Chemical genomics approach to identify genes associated with sensitivity to rapamycin in the fission yeast Schizosaccharomyces pombe.

Rapamycin and its derivatives have now emerged as an attractive therapeutic strategy with both immunosuppressant and antitumor properties. In addition, rapamycin has been proposed as a calorie restriction mimetic to extend the life span of various organisms. The fission yeast Schizosaccharomyces pombe (S. pombe) serves as a valuable genetic model system to study the mechanism(s) of drug action as well as to determine genetic contexts associated with drug sensitivity or resistance. Here, we identified genes that when deleted modulate the rapamycin-sensitive strains in S. pombe. We carried out a chemical genomics screen for rapamycin-sensitive mutants using the genome-deletion library which covers 95.3% of all nonessential fission yeast genes and confirmed 59 genes to be rapamycin sensitive. Gene Ontology (GO) enrichment analysis showed that strains sensitive to rapamycin are highly enriched in processes regulating tRNA modification and mitochondria as well as other ontologies, including cellular metabolic process, chromatin organization, cell cycle, signaling, translation, transport and other cellular processes. Analysis also showed that components of the Elongator complex are overrepresented in the sensitive strains. Here, the data obtained will provide valuable information for speculation on the actions of rapamycin as well as on TORC signaling, thereby presenting a strategy to enhance sensitivity to rapamycin.

Risk factors for active bleeding from colonic angiodysplasia confirmed by colonoscopic observation.

PURPOSE: Colonic angiodysplasia is an important cause of lower gastrointestinal bleeding in the elderly. Here, we investigated the risk factors for bleeding from colonic angiodysplasia seen at endoscopy. METHODS: We conducted a retrospective case-control study by reviewing records of 435 patients with angiodysplasia at colonoscopy from November 2006 to November 2015 in our hospital. To identify risk factors for active bleeding, the following were analyzed: age, sex, comorbidities, use of antithrombotic drugs and non-steroidal anti-inflammatory drugs, and the size and location of the lesions. RESULTS: Among the 435 patients, active bleeding from angiodysplasia was observed at endoscopy in 29 patients (6.7 %). Using multivariate analysis, we identified advanced age (odds ratio 5.15, 95 % confidence interval, 1.61-16.5), comorbidity of heart disease (6.88, 1.04-45.5), use of anticoagulant drug (4.22, 1.21-14.7), multiple lesions (6.67, 1.77-25.2), and small lesions (≤5 mm) (17.7, 4.90-64.0) as independent and significant risk factors for active bleeding. Actively bleeding colonic angiodysplasia lesions were very small in most cases (1-2 mm, 24/29, 83 %) and predominantly located in the right-side colon (26/29, 90 %). All of the 29 patients with active bleeding were successfully and safely treated endoscopically, but re-bleeding occurred in nine patients (31 %, 9/29) during the follow-up period of 2-84 months. CONCLUSIONS: Multiple and small colonic angiodysplasia lesions in patients of advanced age, with heart disease, or receiving anticoagulants have increased risk for bleeding. We should be aware that small colonic angiodysplasia lesions in the right-side colon at colonoscopy in these patients may be a source of bleeding.

Imp2, the PSTPIP homolog in fission yeast, affects sensitivity to the immunosuppressant FK506 and membrane trafficking in fission yeast.

Cytokinesis is a highly ordered process that divides one cell into two cells, which is functionally linked to the dynamic remodeling of the plasma membrane coordinately with various events such as membrane trafficking. Calcineurin is a highly conserved serine/threonine protein phosphatase, which regulates multiple biological functions, such as membrane trafficking and cytokinesis. Here, we isolated imp2-c3, a mutant allele of the imp2(+) gene, encoding a homolog of the mouse PSTPIP1 (proline-serine-threonine phosphatase interacting protein 1), using a genetic screen for mutations that are synthetically lethal with calcineurin deletion in fission yeast. The imp2-c3 mutants showed a defect in cytokinesis with multi-septated phenotypes, which was further enhanced upon treatment with the calcineurin inhibitor FK506. Notably, electron micrographs revealed that the imp2-c3 mutant cells accumulated aberrant multi-lamella Golgi structures and putative post-Golgi secretory vesicles, and exhibited fragmented vacuoles in addition to thickened septa. Consistently, imp2-c3 mutants showed a reduced secretion of acid phosphatase and defects in vacuole fusion. The imp2-c3 mutant cells exhibited a weakened cell wall, similar to the membrane trafficking mutants identified in the same genetic screen such as ypt3-i5. These findings implicate the PSTPIP1 homolog Imp2 in Golgi/vacuole function, thereby affecting various cellular processes, including cytokinesis and cell integrity.

Functional link between Rab GTPase-mediated membrane trafficking and PI4,5P2 signaling.

Fission yeast its3(+) encodes an essential phosphatidylinositol-4-phosphate 5-kinase (PI4P5K) that regulates cell integrity and cytokinesis. We performed a genetic screen to identify genes that function in PI4P5K-mediated signaling, and identified gyp10(+) encoding a Rab GTPase-activating protein (GAP), a negative regulator for Rab GTPase signaling. Its3 overproduction caused growth defects and abnormal cytoplasmic accumulation of the Its3 protein, which can be stained by calcofluor. Notably, Its3 overproducing cells displayed abnormal membranous structures, multilamella Golgi and fragmented vacuoles showed by Electron microscopy. Furthermore, the excess cytoplasmic Its3 structure partly colocalized with the fluorescence of FM4-64. Gyp10 rescued both growth defects and abnormal Its3 localization when it was over-expressed. Gyp10 functionally interacted with the Rab GTPases Ypt3 and Ryh1, both of which regulate Golgi membrane trafficking. Consistently, mutation or deletion of Ypt3 and Ryh1 suppressed phenotypes associated with Its3 overproduction. Importantly, the plasma membrane localization of Its3 was also affected by the impairment of the Ypt3/Ryh1 Rab membrane trafficking, thus suggesting that membrane trafficking events regulated by two Rab GTPases functionally interacts with PI4,5P2 signaling. These results suggest a mechanism whereby PI4P5K signaling/localization is affected by Golgi membrane trafficking, thus provide a functional link between the PI4,5P2 signaling and Rab-mediated trafficking.