Utility of a Passive Bending Colonoscope for Endoscopic Retrograde Cholangiopancreatography in Patients with Surgically Altered Anatomy.

BACKGROUND AND AIM: The utility of a passive bending colonoscope (PBCS) in ERCP for patients with surgically altered anatomy has not been established. This study compared the outcome of PBCS-ERCP and balloon-assisted enteroscope (BAE)-ERCP. METHODS: This multicenter observational study included 343 patients with surgically altered anatomy who underwent ERCP. Among these, 110 underwent PBCS-ERCP and 233 underwent BAE-ERCP. Propensity score matching was applied, and a final cohort of 210 (105 in each group) with well-balanced backgrounds was analyzed. The primary outcome was the success rate of reaching anastomosis or ampulla of Vater. Secondary endpoints included the cannulation success rate, completion rate, procedure time (to reach, cannulate, complete), and adverse events. RESULTS: The success rate for reaching the target was 91.4% (96/105) with PBCS and 90.5% (95/105) with BAE (odds ratio [95% CI] 1.12, [0.44-2.89], P = 0.809). The mean time required to reach the target was significantly shorter in PBCS: 10.04 min (SD, 9.62) with PBCS versus 18.77 min (SD, 13.21) with BAE (P < 0.001). There were no differences in the success of cannulation or procedure completion, although the required times for cannulation and procedure completion were significantly shorter in PBCS. The incidence of adverse events was significantly higher in BAE (19.0%) than in PBCS (4.8%; P < 0.001). CONCLUSIONS: In patients with surgically altered anatomy, PBCS-ERCP showed promising results with shorter time to reach, cannulate, and a lower incidence of adverse events compared with BAE-ERCP. The success rate of reaching was favorable through PBCS compared with BAE. CLINICAL TRIAL REGISTRATION: UMIN000045546.

The risk of weekend biopsy: Impact of specimen source and fixation status on HER2 assessment in the treatment of advanced gastric cancer (The HER_WEEKEND study).

Accurate evaluation of human epidermal growth factor receptor type 2 (HER2) expression is crucial for determining chemotherapy regimens in gastric cancer. However, formalin fixation status has been identified as an important factor affecting HER2 assessment reliability. This retrospective cohort study aimed to investigate the correlation between sample collection day (weekday vs. weekend) and source (biopsy vs. surgical specimens) in assessing HER2 expression in patients with unresectable advanced/recurrent gastric cancer. Data were collected from gastric cancer patients who received chemotherapy at a single public hospital in Japan from 2008 to 2021. The analysis included 177 patients (109 men, 68 women) with a median age of 68.0 (21-88) years, and the primary outcome was the HER2 positivity rate. The overall HER2 positivity rate was 18.1%, with higher rates on weekdays (20.0%) compared to weekends (12.8%). Biopsies had higher positivity rates on weekdays (23.9%) but lower rates on weekends (11.1%) than surgical specimens. Significant differences were observed in formalin fixation times between weekdays and weekends for both biopsies and surgical samples. The study findings suggest that longer formalin fixation times on weekends may lead to underestimating HER2 expression, particularly in biopsies. Therefore, it is crucial to be cautious of excessive formalin fixation when collecting samples, especially during weekend biopsies.

Identification of α-Tocopherol succinate as an RFFL-substrate interaction inhibitor inducing peripheral CFTR stabilization and apoptosis.

The E3 ubiquitin ligase RFFL is an apoptotic inhibitor highly expressed in cancers and its knockdown suppresses cancer cell growth and sensitizes to chemotherapy. RFFL also participates in peripheral protein quality control which removes the functional cell surface ΔF508-CFTR channel and reduces the efficacy of pharmaceutical therapy for cystic fibrosis (CF). Although RFFL inhibitors have therapeutic potential for both cancer and CF, they remain undiscovered. Here, a chemical array screening has identified α-tocopherol succinate (αTOS) as an RFFL ligand. NMR analysis revealed that αTOS directly binds to RFFL's substrate-binding region without affecting the E3 enzymatic activity. Consequently, αTOS inhibits the RFFL-substrate interaction, ΔF508-CFTR ubiquitination and elimination from the plasma membrane of epithelial cells, resulting in the increased functional CFTR channel. Among the α-tocopherol (αTOL) analogs we tested, only αTOS inhibited the RFFL-substrate interaction and increased the cell surface ΔF508-CFTR, depending on RFFL expression. Similarly, the unique proapoptotic effect of αTOS was dependent on RFFL expression. Thus, unlike other αTOL analogs, αTOS acts as an RFFL protein-protein interaction inhibitor which may explain its unique biological properties among αTOL analogs. Moreover, αTOS may act as a CFTR stabilizer, a novel class of drugs that extend cell surface ΔF508-CFTR lifetime.

Improvement of detection sensitivity of upper gastrointestinal epithelial neoplasia in linked color imaging based on data of eye tracking.

BACKGROUND AND AIM: Linked color imaging (LCI) is useful for screening in the gastrointestinal tract; however, its true clinical benefit has not been determined. The aim of this study was to determine the objective advantage of LCI for detection of upper gastrointestinal neoplasms. METHODS: Nine endoscopists, including three novices, three trainees, and three experts, prospectively performed eye tracking. From 30 cases of esophageal or gastric neoplasm and 30 normal cases without neoplasms, a total of 120 images, including 60 pair images of white light imaging (WLI) and LCI taken at the same positions and angles, were randomly shown for 10 s. The sensitivity of tumor detection as a primary endpoint was evaluated and sensitivities by organ, size, and visual gaze pattern were also assessed. Color differences (ΔE using CIE1976 [L*a*b*]) between lesions and surrounding mucosa were measured and compared with detectability. RESULTS: A total of 1080 experiments were completed. The sensitivities of tumor detection in WLI and LCI were 53.7% (50.1-56.8%) and 68.1% (64.8-70.8%), respectively (P = 0.002). LCI provided higher sensitivity than WLI for the novice and trainee groups (novice: 42.2% [WLI] vs 65.6% [LCI], P = 0.003; trainee: 54.4% vs 70.0%, P = 0.045). No significant correlations were found between sensitivity and visual gaze patterns. LCI significantly increased ΔE, and the diagnostic accuracy with WLI depended on ΔE. CONCLUSIONS: In conclusion, LCI significantly improved sensitivity in the detection of epithelial neoplasia and enabled epithelial neoplasia detection that is not possible with the small color difference in WLI. (UMIN000047944).

An Autopsy Case of Rapidly Aggravated Clostridium perfringens Septicemia with Colorectal Cancer.

This report presents a case of a 60-year-old man who was diagnosed with ascending colon cancer with metastases of the lymph nodes and multiple liver metastases. Three days before the introduction of the first chemotherapy, he visited our hospital due to high fever. The blood test revealed an increase in the inflammatory response, hepatobiliary enzyme level, lactate dehydrogenase (LDH) level, and renal function deterioration. Contrast-enhanced computed tomography (CT) showed a rapid progression of primary lesion and liver metastatic lesions. Treatment with 5-fluorouracil, leucovorin, and oxaliplatin and cetuximab (FOLFOX/Cmab) was initiated, and the patient was admitted to our hospital after the first day of chemotherapy. At midnight, he had chills, red urine, and rapid hypoxemia. The second blood test showed progression of anemia; increased total bilirubin, aspartate aminotransferase, and LDH levels; and decreased platelet and fibrinogen levels. The serum was red wine in color, indicating marked hemolysis. The respiratory condition rapidly deteriorated, and tracheal intubation was performed and transferred into the intensive care unit. However, blood oxygenation did not increase, and the patient died the next morning, 19 h after admission, despite intensive care. Postmortem CT showed intraperitoneal free air and gas retention in the liver tumor and portal vein system. Pathological autopsy revealed perforation in ascending colon cancer, many Gram-positive rods in the perforation site, dissemination of bacteria throughout the body, and diffuse pulmonary edema. Subsequently, blood cultures reported Clostridium perfringens (CP), which is a product of alpha-toxin. CP infection can cause rapid aggravation and sudden death. The physicians should be aware of this highly fatal infection, leading to immediate diagnosis and treatment.

The Ubiquitin Ligase RNF34 Participates in the Peripheral Quality Control of CFTR (RNF34 Role in CFTR PeriQC).

The peripheral protein quality control (periQC) system eliminates the conformationally defective cystic fibrosis transmembrane conductance regulator (CFTR), including ∆F508-CFTR, from the plasma membrane (PM) and limits the efficacy of pharmacological therapy for cystic fibrosis (CF). The ubiquitin (Ub) ligase RFFL is responsible for the chaperone-independent ubiquitination and lysosomal degradation of CFTR in the periQC. Here, we report that the Ub ligase RNF34 participates in the CFTR periQC in parallel to RFFL. An in vitro study reveals that RNF34 directly recognizes the CFTR NBD1 and selectively promotes the ubiquitination of unfolded proteins. RNF34 was localized in the cytoplasm and endosomes, where RFFL was equally colocalized. RNF34 ablation increased the PM density as well as the mature form of ∆F508-CFTR rescued at low temperatures. RFFL ablation, with the exception of RNF34 ablation, increased the functional PM expression of ∆F508-CFTR upon a triple combination of CFTR modulators (Trikafta) treatment by inhibiting the K63-linked polyubiquitination. Interestingly, simultaneous ablation of RNF34 and RFFL dramatically increased the functional PM ∆F508-CFTR by inhibiting the ubiquitination in the post-Golgi compartments. The CFTR-NLuc assay demonstrates that simultaneous ablation of RNF34 and RFFL dramatically inhibits the degradation of mature ∆F508-CFTR after Trikafta treatment. Therefore, these results suggest that RNF34 plays a crucial role in the CFTR periQC, especially when there is insufficient RFFL. We propose that simultaneous inhibition of RFFL and RNF34 may improve the efficacy of CFTR modulators.

Efficacy of a novel in ovo-attenuated live vaccine and recombinant vaccine against a very virulent infectious bursal disease virus in chickens.

Infectious bursal disease (IBD) causes severe economic damage to the poultry industry worldwide. To prevent IBD virus (IBDV) infection, live virus vaccines have been widely used in chickens having wide-ranging levels of maternally derived antibodies. But, the risks of infection with other pathogens because of lesions related to atrophy of the bursa of Fabricius in vaccinated chickens are a concern. To resolve the problems, a recombinant turkey herpesvirus (HVT) vaccine expressing IBDV-VP2 protein (rHVT-IBD) has been developed. However, the induction of neutralizing antibodies by rHVT-IBD against a virulent IBDV might be delayed compared with that by the live IBD vaccine, leading to the high risks of IBDV infection for young chickens. To find the best selection of IBDV vaccine for the onset of immunity, we examine the protective efficacy of a novel in ovo-attenuated live IBDV (IBD-CA) vaccine and the rHVT-IBD vaccine in young chickens challenged with a very virulent IBDV (vvIBDV) strain. We show that the protective efficacy of IBD-CA vaccine was higher than that of the rHVT-IBD vaccine in 14-day-old chickens challenged with the vvIBDV strain, leading to the risk of IBDV infection for young chickens when vaccinated with rHVT-IBD. Our results suggest that farmers should select the best vaccines to maximize vaccine efficacy in consideration of the vaccine characteristics, prevalence levels of IBDV in the areas, and initial MDA levels of the chickens since the attenuated live and recombinant vaccines play a role in the different vaccine efficacies.

Incidence of cancer-associated thromboembolism in Japanese gastric and colorectal cancer patients receiving chemotherapy: a single-institutional retrospective cohort analysis (Sapporo CAT study).

OBJECTIVE: Few data regarding the incidence of cancer-associated thromboembolism (TE) are available for Asian populations. We investigated the incidence of TE (TEi) and its risk factors among gastric and colorectal cancer (GCC) patients received chemotherapy in a daily practice setting. DESIGN: A retrospective cohort study. SETTING: A single-institutional study that used data from Sapporo City General Hospital, Japan, on patients treated between January 2008 and May 2015. PARTICIPANTS: Five hundred Japanese GCC patients who started chemotherapy from January 2008 to May 2015. PRIMARY AND SECONDARY OUTCOME MEASURES: TE was diagnosed by reviewing all the reports of contrast-enhanced CT performed during the follow-up period. All types of thrombosis detected by CT or additional imaging tests, such as venous TE, arterial TE and cerebral infarction, were defined as TE. Medical records of all identified patients were reviewed and potential risk factors for TE, including clinicopathological backgrounds, were collected. We defined the following patients as 'active cancer'; patients with unresectable advanced GCC, cancer recurrence during or after completing adjuvant chemotherapy and/or presence of other malignant tumours. RESULTS: Of the 500 patients, 70 patients (14.0%) developed TE during the follow-up period. TEi was 9.2% and 17.3% in GCC patients, 18.1% and 3.5% in active and non-active cancer patients, and 24.0% and 12.9% in multiple and single primary, respectively. Multivariate logistic regression analysis showed that colorectal cancer (CRC) (OR 2.371; 95% CI 1.328 to 4.233), active cancer (OR 7.593; 95% CI 2.950 to 19.543) and multiple primary (OR 2.527; 95% CI 1.189 to 5.370) were independently associated with TEi. CONCLUSION: TEi was 14.0% among Japanese GCC patients received chemotherapy, and was significantly higher among patients with CRC, active cancer and multiple primary than among those with gastric cancer, non-active cancer and single primary, respectively. TRIAL REGISTRATION NUMBER: UMIN000018912.

The integral function of the endocytic recycling compartment is regulated by RFFL-mediated ubiquitylation of Rab11 effectors.

Endocytic trafficking is regulated by ubiquitylation (also known as ubiquitination) of cargoes and endocytic machineries. The role of ubiquitylation in lysosomal delivery has been well documented, but its role in the recycling pathway is largely unknown. Here, we report that the ubiquitin (Ub) ligase RFFL regulates ubiquitylation of endocytic recycling regulators. An RFFL dominant-negative (DN) mutant induced clustering of endocytic recycling compartments (ERCs) and delayed endocytic cargo recycling without affecting lysosomal traffic. A BioID RFFL interactome analysis revealed that RFFL interacts with the Rab11 effectors EHD1, MICALL1 and class I Rab11-FIPs. The RFFL DN mutant strongly captured these Rab11 effectors and inhibited their ubiquitylation. The prolonged interaction of RFFL with Rab11 effectors was sufficient to induce the clustered ERC phenotype and to delay cargo recycling. RFFL directly ubiquitylates these Rab11 effectors in vitro, but RFFL knockout (KO) only reduced the ubiquitylation of Rab11-FIP1. RFFL KO had a minimal effect on the ubiquitylation of EHD1, MICALL1, and Rab11-FIP2, and failed to delay transferrin recycling. These results suggest that multiple Ub ligases including RFFL regulate the ubiquitylation of Rab11 effectors, determining the integral function of the ERC.

Safety and efficacy of sofosbuvir and ribavirin for genotype 2 hepatitis C Japanese patients with renal dysfunction.

AIM: The safety and efficacy of sofosbuvir (SOF) and ribavirin (RBV) have not been well clarified in patients with renal dysfunction because clinical trials have not included such patients. We evaluated the safety and efficacy of SOF and RBV for genotype 2 hepatitis C virus (HCV)-infected patients with renal dysfunction. METHODS: The study included genotype 2 HCV-infected patients who received SOF and RBV between July 2014 and May 2017. The sustained virologic response (SVR) after the treatment and safety during the therapy were evaluated according to renal function. RESULTS: A total of 231 patients were included in this study. The median age was 62 years old, and 45.9% (106/231) were men. Of the 231 patients, 191 (82.8%) and 40 (17.2%) were classified as having chronic kidney disease (CKD) stages G1/2 and G3, respectively. The overall SVR rate was 97% (224/231). The SVR rates in patients with CKD stages G1, 2, G3a, and G3b were 98.1%, 98.6%, 87.9%, and 100%, respectively, and this therapy was tolerated. Multivariate analysis indicated that renal dysfunction was significantly associated with a non-SVR (odds ratio, 6.963; 95% confidence interval, 1.494-32.41; P = 0.013). The patients with renal dysfunction were older, had advanced liver fibrosis, lower baseline platelet and hemoglobin levels, and a higher rate of RBV dose reduction. CONCLUSIONS: Sofosbuvir and RBV therapy is highly effective and safe for genotype 2 HCV-infected Japanese patients. However, attention should be paid to baseline renal function when SOF- and RBV-containing regimens are used for patients with renal dysfunction.

Nanoporosity Change on Elastic Relaxation of Partially Folded Graphene Monoliths.

Fabrication of nanographene shows a promising route for production of designed porous carbons, which is indispensable for highly efficient molecular separation and energy storage applications. This process requires a better understanding of the mechanical properties of nanographene in their aggregated structure. We studied the structural and mechanical properties of nanographene monoliths compressed at 43 MPa over different times from 3 to 25 h. While in monoliths compressed over shorter time adsorption isotherms of Ar at 87 K or N2 at 77 K exhibited a prominent hysteresis due to presence of predominant mesopores, compression for long time induces a low pressure hysteresis. On the other hand, compression for 25 h increases the microporosity evaluated by Ar adsorption, not by N2 adsorption, indicating that 25 h compression rearranges the nanographene stacking structure to produce ultramicropores that can be accessible only for Ar. TEM, X-ray diffraction, and Raman spectroscopic studies indicated that the compression for 25 h unfolds double-bent-like structures, relaxing the unstable nanographene stacked structure formed on the initial compression without nanographene sheets collapse. This behavior stems from the highly elastic nature of the nanographenes.

Adsorption-desorption mediated separation of low concentrated D2O from water with hydrophobic activated carbon fiber.

The adsorption and desorption of D2O on hydrophobic activated carbon fiber (ACF) occurs at a smaller pressure than the adsorption and desorption of H2O. The behavior of the critical desorption pressure difference between D2O and H2O in the pressure range of 1.25-1.80kPa is applied to separate low concentrated D2O from water using the hydrophobic ACF, because the desorption branches of D2O and H2O drop almost vertically. The deuterium concentration of all desorbed water in the above pressure range is lower than that of water without adsorption-treatment on ACF. The single adsorption-desorption procedure on ACF at 1.66kPa corresponding to the maximum difference of adsorption amount between D2O and H2O reduced the deuterium concentration of desorbed water to 130.6ppm from 143.0ppm. Thus, the adsorption-desorption procedure of water on ACF is a promising separation and concentration method of low concentrated D2O from water.

Low-cesium rice: mutation in OsSOS2 reduces radiocesium in rice grains.

In Japan, radiocesium contamination in foods has become of great concern and it is a primary issue to reduce grain radiocesium concentration in rice (Oryza sativa L.). Here, we report a low-cesium rice mutant 1 (lcs1) with the radiocesium concentration in grain about half that in the wild-type cultivar. Genetic analyses revealed that a mutation in OsSOS2, which encodes a serine/threonine-protein kinase required for the salt overly sensitive (SOS) pathway in plants, is responsible for the decreased cesium (Cs) concentrations in lcs1. Physiological analyses showed that Cs+ uptake by lcs1 roots was significantly decreased under low-potassium (K+) conditions in the presence of sodium (Na+) (low K+/Na+). The transcript levels of several K+ and Na+ transporter genes, such as OsHAK1, OsHAK5, OsAKT1, and OsHKT2;1 were significantly down-regulated in lcs1 grown at low K+/Na+. The decreased Cs+ uptake in lcs1 might be closely related to the lower expression of these genes due to the K+/Na+ imbalance in the lcs1 roots caused by the OsSOS2 mutation. Since the lcs1 plant had no significant negative effects on agronomic traits when grown in radiocesium-contaminated paddy fields, this mutant could be used directly in agriculture for reducing radiocesium in rice grains.

A Prospective Observational Study on Effect of Short-Term Periodic Steroid Premedication on Bone Metabolism in Gastrointestinal Cancer (ESPRESSO-01).

BACKGROUND: A multicenter prospective observational study evaluated the effect of gastrointestinal cancer chemotherapy with short-term periodic steroid premedication on bone metabolism. PATIENTS AND METHODS: Seventy-four patients undergoing chemotherapy for gastrointestinal cancer were studied. The primary endpoints were changes in bone mineral densities (BMDs) and metabolic bone turnover 16 weeks after initiation of chemotherapy. BMDs, measured by dual-energy x-ray absorptiometry, and serum cross-linked N-telopeptides of type I collagen (sNTX), and bone alkaline phosphatase (sBAP) were assessed for evaluation of bone resorption and formation, respectively. RESULTS: In 74.3% (55/74) of the patients, BMDs were significantly reduced at 16 weeks relative to baseline. The percent changes of BMD were -1.89% (95% confidence interval [CI], -2.67% to -1.11%: p < .0001) in the lumbar spine, -2.24% (95% CI, -3.59% to -0.89%: p = .002) in the total hip, and -2.05% (95% CI, -3.11% to -0.99%: p < .0001) in the femoral neck. Although there was no significant difference in sNTX levels during 16 weeks (p = .136), there was a significant increase in sBAP levels (p = .010). Decreased BMD was significantly linked to number of chemotherapy cycles (p = .02). There were no significant correlations between changes in BMDs and the primary site of malignancy, chemotherapy regimens, total cumulative steroid dose, steroid dose intensity, and additive steroid usage. CONCLUSION: Gastrointestinal cancer chemotherapy with periodic glucocorticoid premedication was associated with reduced BMD and increased sBAP levels, which were linked to number of chemotherapy cycles but independent of primary site, chemotherapy regimen, duration, and additive steroid usage. The Oncologist 2017;22:592-600 IMPLICATIONS FOR PRACTICE: Bone health and the management of treatment-related bone loss are important for cancer care. The present study showed that a significant decrease in bone mineral density (BMD) and an increase in serum bone alkaline phosphatase levels occurred in gastrointestinal cancer patients receiving chemotherapy, which were linked to number of chemotherapy cycles but were independent of primary site, chemotherapy regimen, total steroid dose, and steroid dose intensity. Surprisingly, it seems that the decreasing BMD levels after only 16 weeks of chemotherapy for gastrointestinal cancer were comparable to that of 12-month adjuvant aromatase inhibitor therapy for early-stage breast cancer patients.