Anterior resection syndrome: a randomized clinical trial of a 5-HT3 receptor antagonist (ramosetron) in male patients with rectal cancer.

BACKGROUND: No effective treatment exists for anterior resection syndrome (ARS) following sphincter-saving surgery for rectal cancer. This RCT assessed the safety and efficacy of a 5-HT3 receptor antagonist, ramosetron, for ARS. METHODS: A single-centre, randomized, controlled, open-label, parallel group trial was conducted. Male patients with ARS 1 month after rectal cancer surgery or ileostomy reversal were enrolled and randomly assigned (1 : 1) to 5 µg of ramosetron (Irribow®) daily or conservative treatment for 4 weeks. Low ARS (LARS) score was calculated after randomization and 4 weeks after treatment. The study was designed as a superiority test with a primary endpoint of the proportion of patients with major LARS between the groups. Primary outcome analysis was based on the modified intention-to-treat population. Safety was assessed by monitoring adverse events during the study. RESULTS: : A total of 100 patients were randomized to the ramosetron (49 patients) or conservative treatment group (51 patients). Two patients were excluded, and 48 and 50 patients were analysed in the ramosetron and control groups, respectively. The proportion of major LARS after 4 weeks was 58 per cent (28 of 48 patients) in the ramosetron group versus 82 per cent (41 of 50 patients) in the control group, with a difference of 23.7 per cent (95 per cent c.i. 5.58 to 39.98, P = 0.011). There were minor adverse events in five patients, which were hard stool, frequent stool or anal pain. These were not different between the two groups. There were no serious adverse events. CONCLUSION: : Ramosetron could be safe and feasible for male patients with ARS. TRIAL REGISTRATION NUMBER: NCT02869984 (http://www.clinicaltrials.gov).

Comparison of five membrane filters to collect bioaerosols for airborne microbiome analysis.

AIMS: Recovering DNA of airborne micro-organisms (AM) from air is a challenging task. We compared five membrane filters for bioaerosol sampling-mixed cellulose ester (MCE), polyethersulfone (PES), polyamide (PA), polytetrafluorethylene (PTFE) and polyvinylidene fluoride (PVDF)-based on their bacterial, fungal and eukaryotic DNA recoveries. METHODS AND RESULTS: Bacterial, fungal and eukaryotic populations were quantified using quantitative PCR. With a bacterial consortium, PTFE exhibited the best recovery efficiency (113%), followed by PA (92%), PES (86%), MCE (48%) and PVDF (1%). When filters were compared with air, PA was used as a control to normalize results from the others. The bacterial, fungal and eukaryotic DNA recovery ratios were markedly greater in PES (9·3, 11·5 and 10·3 respectively) than in the remaining. Eukaryotic MiSeq sequencing revealed that PES recovered a more diverse and considerably richer assemblage (richness ratios, 4·97 vs ≤ 1·16 for PES vs the others). Rank abundance distribution analysis showed that distribution tails were longer (>4 times) in PES, but these did not differ between the remaining and PA. Community comparison showed that PES exhibited a lower variation across trials than the PA, while the remaining did not. CONCLUSIONS: PES filter markedly outperformed the other filters in quantitative and qualitative recovery of AM. SIGNIFICANCE AND IMPACT OF THE STUDY: Our findings demonstrated the importance of filter selection for sampling AM.

Effects of quorum quenching on temporal succession of activated sludge microbial community in a membrane bioreactor.

AIMS: Quorum quenching (QQ) is an attractive strategy for mitigating biofouling in membrane bioreactors (MBRs). However, the effects of QQ on the activated sludge (AS) process have not been adequately evaluated. This study investigated the long-term effects of QQ on a laboratory-scale anoxic-oxic MBR, focusing on AS performance and microbial community. METHODS AND RESULTS: Anoxic-oxic MBRs with and without QQ were operated for 91 days. QQ did not affect COD and TN removal efficiencies over the experimental period, during which its activity remained >90%. QQ reduced floc size by approximately 8% but had no effect on biomass concentration. AS microbial communities were regularly analysed using massively parallel sequencing. AS bacterial communities were temporally dynamic irrespective of QQ presence, for example, a temporal increase in bacterial diversity and a temporal decay of community similarity. QQ counteracted the temporal change in diversity and the temporal distance-community decay. Community comparison revealed that QQ changed the successional trajectory of the AS community at a late period, because it decelerated temporal changes of specific members, such as Thiothrix and Sphingomonadaceae*. Correlation networks revealed that QQ increased network clustering, complexity and density. The combined results suggest that the tighter microbial association by QQ increased the community resistance. CONCLUSIONS: QQ can enhance the diversity and stability of the AS community in MBR by counteracting the innate temporal change in community structure. SIGNIFICANCE AND IMPACT OF THE STUDY: Our findings are useful for the further advancement of QQ-based strategies in engineered microbial environments.

Predictors of permanent stoma creation in patients with mid or low rectal cancer: results of a multicentre cohort study with preoperative evaluation of anal function.

AIM: Preoperative factors predictive of permanent stoma creation were investigated in a long-term follow-up of patients with mid or low rectal cancer. METHOD: We included patients who underwent radical resection for mid or low rectal cancer with available data for preoperative anal function measured by manometry and Faecal Incontinence Severity Index questionnaire between January 2005 and December 2015 in three tertiary referral hospitals. A permanent stoma was defined as a stoma present until the patient's last follow-up visit or death. Preoperative factors that predicted permanent stoma creation were analysed. RESULTS: Over a median follow-up of 57.4 months (range 12-143 months), a permanent stoma was created in 144/577 (25.0%) patients, including 89 (15.4%) who underwent abdominoperineal resection, one (0.2%) who underwent Hartmann's operation without reversal, 15 (2.6%) with a diverting ileostomy at the time of initial sphincter-preserving surgery without undergoing stoma reversal, and 39 (6.8%) who underwent permanent ileostomy formation after sphincter-preserving surgery. Patients with permanent stoma creation had a shorter tumour distance from the anal verge (P < 0.001), larger tumour size (P = 0.020) and higher preoperative Faecal Incontinence Severity Index score (P = 0.020). On multivariable analysis, tumour distance from the anal verge predicted permanent stoma formation (relative risk 0.53 per centimetre increase; 95% confidence interval 0.46-0.60; P < 0.001) but preoperative anal function did not. CONCLUSION: Tumour distance from the anal verge was the only preoperative determinant of permanent stoma creation in rectal cancer patients. These data may help mid and low rectal cancer patients understand the need for permanent stoma.

Development of a novel methanotrophic process with the helper micro-organism Hyphomicrobium sp. NM3.

AIMS: Microbial consortia can be more efficient at biological processes than single isolates. The purposes of this study were to design and evaluate a synthetic microbial consortium containing the methanotroph Methylocystis sp. M6 and the helper Hyphomicrobium sp. NM3, and develop a novel methanotrophic process for this consortium utilizing a dialysis membrane. METHODS AND RESULTS: Hyphomicrobium increased the methane-oxidation rate (MOR), biomass and stability at a dilution rate of 0·067 day-1 in fed-batch co-culture. qRT-PCR showed that Methylocystis population increased gradually with time, whereas Hyphomicrobium population remained stable despite cell washing, confirming synergistic population interaction. At 0·1 day-1 , spiking of Hyphomicrobium effectively increased the methanotrophic activity, after which Hyphomicrobium population decreased with time, indicating that the consortium is optimal at <0·1 day-1 . When Hyphomicrobium was grown in dialysis membrane within the bioreactor, MOR increased linearly up to 155·1 ± 1·0 mmol l-1  day-1 at 0·067, 0·1, 0·2 and 0·4 day-1 , which is the highest observed value for a methanotrophic reactor. CONCLUSIONS: Hyphomicrobium sp. NM3 is a promising helper micro-organism for methanotrophs. Hyphomicrobium-methanotroph consortia used concurrently with existing methods can produce an efficient and stable methane oxidation system. SIGNIFICANCE AND IMPACT OF THE STUDY: This novel methanotrophic process is superior to those previously reported in the literature, and can provide efficient and stable methane oxidation.

Musashi RNA-binding protein 2 regulates estrogen receptor 1 function in breast cancer.

Musashi RNA-binding protein 2 (MSI2) has important roles in human cancer. However, the regulatory mechanisms by which MSI2 alters breast cancer pathophysiology have not been clearly identified. Here we demonstrate that MSI2 directly regulates estrogen receptor 1 (ESR1), which is a well-known therapeutic target and has been shown to reflect clinical outcomes in breast cancer. Based on gene expression data analysis, we found that MSI2 expression was highly enriched in estrogen receptor (ER)-positive breast cancer and that MSI2 expression was significantly correlated with ESR1 expression, including expression of ESR1 downstream target genes. In addition, MSI2 levels were associated with clinical outcomes. MSI2 influenced breast cancer cell growth by altering ESR1 function. MSI2 alters ESR1 by binding specific sites in ESR1 RNA and by increasing ESR1 protein stability. Taken together, our findings identified a novel regulatory mechanism of MSI2 as an upstream regulator of ESR1 and revealed the clinical relevance of the RNA-binding protein MSI2 in breast cancer.

Low Frequency of MKRN3 Mutations in Central Precocious Puberty Among Korean Girls.

Mutations of MKRN3, the gene encoding makorin RING-finger protein 3, lead to central precocious puberty (CPP). The aim of this study was to investigate mutations of the MKRN3 gene in Korean girls with CPP. Two hundred-sixty Korean girls with idiopathic CPP were included. Auxological and endocrine parameters were measured, and the entire MKRN3 gene was directly sequenced. MKRN3 gene analysis revealed one novel nonsense mutation (p.Gln281 *) and 6 missense variants (p.Ile100Phe, p.Gly196Val, p.Ile204Thr, p.Gln226Pro, p.Lys233Asn, and p.Ser396Arg). The novel nonsense mutation (p.Gln281 *) was a heterozygous C>T nucleotide change (c.841C>T) predicted to result in a truncated protein due to a premature stop codon in the MKRN3 gene. The nonsense mutation (p.Gln281 *) was only identified in one of the girls and her younger brother. Compared to previous reports on MKRN3 mutations in familial and sporadic cases of CPP, the present study reveals a relatively low number of MKRN 3 mutations in Korean girls with CPP. Larger samples of children with CPP and MKRN3 mutations are necessary in order to clarify whether the clinical course of puberty may differ as compared to idiopathic CPP.

Experimental study of the potential hazards of surgical smoke from powered instruments.

BACKGROUND: Many surgical instruments have been replaced with powered devices in open gastrointestinal and laparoscopic surgery. The production of smoke as a result of vaporization of surgical tissue is inevitable, and exposure to surgical smoke is a long-standing concern. These vapours are potentially hazardous to patients and surgical teams. The present research was designed to compare various surgical devices to determine whether viable cells exist in their surgical smoke. METHODS: The search for viable cells in surgical smoke was conducted using both in vitro and in vivo experiments. Various cancers were cauterized with electrocautery, radiofrequency ablation and ultrasonic scalpels, and the resulting surgical smoke was aspirated with Transwell(®) membrane; viable cells were sought in the surgical smoke. In an in vivo experiment, samples of SCC7 were cauterized with an ultrasonic scalpel and the sediment from the rinsed Transwell(®) membrane liquid after centrifugation was injected subcutaneously into the lower back of mice. RESULTS: Viable cells were found only in the smoke from ultrasonic scalpels (in all 25 samples taken 5 cm from the cautery; 2 of 25 samples at 10 cm). Viable cells in the surgical smoke from ultrasonic scalpels implanted in mice grew in 16 of 40 injection sites. Histological and biochemical analyses revealed that these cancer cells were identical to the cancer cells cauterized by the ultrasonic scalpel. CONCLUSION: Viable tumour cells are produced in the surgical smoke from tumour dissection by ultrasonic scalpel. Surgical relevance Surgical smoke is a byproduct of dissection using a number of powered devices. Hazards to operating room personnel and patients are unclear. This study has shown that use of an ultrasonic dissection device can produce smoke that contains viable tumour cells. Although the model is somewhat artificial, a theoretical risk exists, and measures to evacuate surgical smoke efficiently are important.

Pathologically proven infective endocarditis demonstrated on 18F-FDG PET/CT / Endocarditis infecciosa patológicamente probada demostrada en 18F-FDG PET/TC

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Retinal pigment epithelial cells undergoing mitotic catastrophe are vulnerable to autophagy inhibition.

The increased mitochondrial DNA damage leads to altered functional capacities of retinal pigment epithelial (RPE) cells. A previous study showed the increased autophagy in RPE cells caused by low concentrations of rotenone, a selective inhibitor of mitochondrial complex I. However, the mechanism by which autophagy regulates RPE cell death is still unclear. In the present study, we examined the mechanism underlying the regulation of RPE cell death through the inhibition of mitochondrial complex I. We report herein that rotenone induced mitotic catastrophe (MC) in RPE cells. We further observed an increased level of autophagy in the RPE cells undergoing MC (RPE-MC cells). Importantly, autophagy inhibition induced nonapoptotic cell death in RPE-MC cells. These findings indicate that autophagy has a pivotal role in the survival of RPE-MC cells. We next observed PINK1 accumulation in the mitochondrial membrane and parkin translocation into the mitochondria from the cytosol in the rotenone-treated RPE-MC cells, which indicates that increased mitophagy accompanies MC in ARPE-19 cells. Noticeably, the mitophagy also contributed to the cytoprotection of RPE-MC cells. Although there might be a significant gap in the roles of autophagy and mitophagy in the RPE cells in vivo, our in vitro study suggests that autophagy and mitophagy presumably prevent the RPE-MC cells from plunging into cell death, resulting in the prevention of RPE cell loss.

Scintigraphic demonstrations of a retrosternal goiter / Descripción gammagráfica de un bocio retroesternal

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Inactivation of the lpcC gene alters surface-related properties and symbiotic capability of Bradyrhizobium japonicum.

UNLABELLED: We investigated the role of the Bradyrhizobium japonicum lpcC gene, encoding a mannosyl transferase, involved in the lipopolysaccharide (LPS) biosynthesis. The inactivation of the lpcC gene considerably altered the LPS structure and the cell surface properties. LPS analysis showed that the lpcC mutant JS715 had an abnormal LPS structure deficient in O-antigen. The cell surface hydrophobicity increased approximately threefold in JS715 compared to the wild type. The increased cell surface hydrophobicity is likely to be related with cell aggregation in the mutant culture. For the growth comparison, JS715 showed slower growth rate than the wild type. The motility of JS715 decreased in soft agar plates, but it showed enhanced biofilm-forming ability. Interestingly, JS715 was not able to nodulate the host legume soybean (Glycine max). This study shows not only that lpcC is involved in the biosynthesis of O-antigen in the B. japonicum LPS, but also that inactivation of the lpcC gene affects symbiotic capability of B. japonicum and surface-related properties such as cell hydrophobicity, biofilm formation and motility. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrates the role of the B. japonicum lpcC in nodulation with soybean and importance of cell surface hydrophobicity. The results also highlight that intact LPS is required for successful symbiosis between B. japonicum and soybeans. Our findings not only support previous studies emphasizing the necessity of LPS on the interaction between the two symbiotic partners, but also contribute to a better understanding of the symbiotic mechanisms.

p34 is a novel regulator of the oncogenic behavior of NEDD4-1 and PTEN.

PTEN is one of the most frequently mutated or deleted tumor suppressors in human cancers. NEDD4-1 was recently identified as the E3 ubiquitin ligase for PTEN; however, a number of important questions remain regarding the role of ubiquitination in regulating PTEN function and the mechanisms by which PTEN ubiquitination is regulated. In the present study, we demonstrated that p34, which was identified as a binding partner of NEDD4-1, controls PTEN ubiquitination by regulating NEDD4-1 protein stability. p34 interacts with the WW1 domain of NEDD4-1, an interaction that enhances NEDD4-1 stability. Expression of p34 promotes PTEN poly-ubiquitination, leading to PTEN protein degradation, whereas p34 knockdown results in PTEN mono-ubiquitination. Notably, an inverse correlation between PTEN and p34/NEDD4-1 levels was confirmed in tumor samples from colon cancer patients. Thus, p34 acts as a key regulator of the oncogenic behavior of NEDD4-1 and PTEN.

Prognostic implication of mucinous histology in colorectal cancer patients treated with adjuvant FOLFOX chemotherapy.

BACKGROUND: There have been controversies in prognostic impact of mucinous histology on colorectal cancer, and its implication in patients treated with adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) is unclear. METHODS: Stage II and III colorectal cancer patients who underwent curative resection followed by adjuvant FOLFOX were included. Patients were grouped according to the mucinous content: >50%, mucinous adenocarcinoma (MAC); <50%, adenocarcinoma with intermediated mucinous component (AIM); and without any mucinous component, non-MAC (NMA). Clinicopathological features and disease-free survival (DFS) were compared. RESULTS: Among a total of 521 patients, 27 patients (5.2%) had MAC, 41 patients (7.9%) had AIM, and 453 patients (86.9%) had NMA. Mucinous adenocarcinoma and AIM had higher frequency of proximal location and microsatellite instability, but lower frequency of angiolymphatic invasion. Disease-free survival was significantly worse in the MAC compared with NMA (3-year DFS 57% and 86%, respectively; P<0.001) and AIM (3-year DFS 87%, P=0.01 vs MAC). Multivariate analysis revealed MAC as an independent negative prognostic factor of DFS (adjusted hazard ratio 7.96, 95% confidence interval 3.76-16.8). CONCLUSION: Adenocarcinoma with intermediated mucinous component and MAC have distinct clinicopathological features compared with NMA. Mucinous adenocarcinoma has an adverse prognostic impact on stage II or III colorectal cancer treated with adjuvant FOLFOX.

The beneficial effect of palliative resection in metastatic colorectal cancer.

BACKGROUND: We aimed to determine the role of palliative resection in metastatic colorectal cancer (mCRC) and ascertain which patient populations would benefit most from this treatment. METHODS: A total of 1015 patients diagnosed with mCRC at Seoul National University Hospital between 2000 and 2009 were retrospectively studied. RESULTS: Of the 1015 patients, 168 patients with only liver and/or lung metastasis received curative resection. The remaining 847 patients were treated with palliative chemotherapy and/or palliative resection combined with best supportive care. Palliative resection was performed in 527 (62.2%) cases (complete resection with negative margin (R0) in 93, R1/2 in 434). Resected patients had a more prolonged median overall survival (OS) than unresected patients (21.3 vs 14.1 months; P<0.001). In multivariate analysis, R0 resection was found to be associated with a superior OS compared with R1/2 resection (51.3 vs 19.1 months; P<0.001) and no resection (51.3 vs 14.1 months; P<0.001). When we performed propensity score matching, palliative resection was found to be related to prolonged OS (hazard ratio=0.72, 95% confidence interval=0.59-0.89; P=0.003). CONCLUSION: Palliative resection without residual disease and chemotherapy confers a longer-term survival outcome than palliative chemotherapy alone in mCRC patient subset.

Comparative study of NOTES rectosigmoidectomy in a swine model: E-NOTES vs. P-NOTES.

BACKGROUND AND STUDY AIMS: Several reports have demonstrated the safety of pure natural-orifice transluminal endoscopic surgery (P-NOTES) using transanal endoscopic microsurgery (TEM) and embryonic NOTES (E-NOTES; laparoscopic surgery through the umbilicus). This study was performed to compare the safety and applicability of NOTES rectosigmoidectomy between E-NOTES and P-NOTES in a swine model. PATIENTS AND METHODS: E-NOTES was conducted through a single port using laparoscopic instruments (n = 11). P-NOTES was performed using TEM with transgastric endoscopic assistance (n = 11). Gastrotomies were created using a needle knife and the balloon dilatation technique, and closed using T-anchors. Blood samples were collected to evaluate changes in systemic cytokine levels during the preoperative and postoperative periods; operative outcomes were also evaluated and compared between the groups. The necropsy findings were recorded after sacrifice at 1 week after the procedure. RESULTS: The mean operative time for P-NOTES was significantly longer than that for E-NOTES (239 vs. 103 minutes, P < 0.001). The mean distance from the anal verge to colorectal anastomosis in the P-NOTES group was significantly less than that in the E-NOTES group (2.9 vs. 17.6 cm, P < 0.001). On necropsy, the complication rate of P-NOTES was higher than that of E-NOTES, but without statistical significance (54.5 % vs. 18.2 %, P = 0.091). The differences in changes in TNF-α, C-reactive protein, interleukin-6, and interleukin-1ß between P-NOTES and E-NOTES were not significant. CONCLUSIONS: E-NOTES rectosigmoidectomy in the swine model is safe, but remains challenging for use in pelvic dissection. P-NOTES rectosigmoidectomy using TEM may be a promising tool for pelvic dissection, but the transgastric approach involves a high degree of risk.

Lack of O-polysaccharide enhances biofilm formation by Bradyrhizobium japonicum.

AIMS: To reveal the effects of the O-polysaccharide antigen of Bradyrhizobium japonicum LPS on biofilm formation and motility. METHODS AND RESULTS: Wild type and O-antigen-deficient mutant strains of B. japonicum were tested for biofilm formation on polyvinyl chloride (PVC) surfaces and motility on semi-solid (0.3%) agar media. After 7 days of incubation, the amount of biofilms formed by the mutant was c. 3.5-fold greater than that of the wild type. Unlike biofilm formation, the motility assay revealed that the mutant strain was less motile than the wild type. CONCLUSIONS: This study shows enhanced biofilm formation and decreased motility by the O-antigen-deficient mutant, suggesting that the lack of the O-polysaccharide of the rhizobial LPS is associated with biofilm-forming ability and movement. SIGNIFICANCE AND IMPACT OF THE STUDY: LPS plays an important role in both pathogenic and beneficial bacteria. It has also been reported that LPS deficiency negatively affects biofilm formation. However, our results demonstrate that the O-antigen-deficient mutant enhances biofilm formation, presumably through a significant increase in hydrophobicity. It is notable that the hydrophobicity of cell walls might be a key regulator in controlling biofilm development in B. japonicum.

Galectin-3 stabilizes heterogeneous nuclear ribonucleoprotein Q to maintain proliferation of human colon cancer cells.

Comparative analysis of proteomes using 5-fluorouracil (5-FU)-resistant human colon cancer cell line revealed that decreased galectin-3 expression was significantly associated with retarded proliferation. However, in the presence of 5-FU proliferation rate of cells with suppressed galectin-3 expression did not differ from that of cells with normal galectin-3 expression, even galectin-3 suppression augmented apoptosis. Mechanism by which galectin-3 regulates cancer cell proliferation has been identified in immunoprecipitates of the anti-galectin-3 antibody. Heterogeneous nuclear ribonucleoprotein Q (hnRNP Q) was identified as a protein interacting with galectin-3. Interestingly, while galectin-3 protein was not affected by the hnRNP Q level, its suppression was accompanied by a decrease in hnRNP Q expression. The present study demonstrates that galectin-3 stabilizes hnRNP Q via complex formation, and reduction in the hnRNP Q level leads to slow proliferation and less susceptibility to 5-FU.