Rectal cancer lateral lymph nodes: multicentre study of the impact of obturator and internal iliac nodes on oncological outcomes.

BACKGROUND: In patients with rectal cancer, enlarged lateral lymph nodes (LLNs) result in increased lateral local recurrence (LLR) and lower cancer-specific survival (CSS) rates, which can be improved with (chemo)radiotherapy ((C)RT) and LLN dissection (LLND). This study investigated whether different LLN locations affect oncological outcomes. METHODS: Patients with low cT3-4 rectal cancer without synchronous distant metastases were included in this multicentre retrospective cohort study. All MRI was re-evaluated, with special attention to LLN involvement and response. RESULTS: More advanced cT and cN category were associated with the occurrence of enlarged obturator nodes. Multivariable analyses showed that a node in the internal iliac compartment with a short-axis (SA) size of at least 7 mm on baseline MRI and over 4 mm after (C)RT was predictive of LLR, compared with a post-(C)RT SA of 4 mm or less (hazard ratio (HR) 5.74, 95 per cent c.i. 2.98 to 11.05 vs HR 1.40, 0.19 to 10.20; P < 0.001). Obturator LLNs with a SA larger than 6 mm after (C)RT were associated with a higher 5-year distant metastasis rate and lowered CSS in patients who did not undergo LLND. The survival difference was not present after LLND. Multivariable analyses found that only cT category (HR 2.22, 1.07 to 4.64; P = 0.033) and margin involvement (HR 2.95, 1.18 to 7.37; P = 0.021) independently predicted the development of metastatic disease. CONCLUSION: Internal iliac LLN enlargement is associated with an increased LLR rate, whereas obturator nodes are associated with more advanced disease with increased distant metastasis and reduced CSS rates. LLND improves local control in persistent internal iliac nodes, and might have a role in controlling systemic spread in persistent obturator nodes.Members of the Lateral Node Study Consortium are co-authors of this study and are listed under the heading Collaborators.

No significant association between stable iodine intake and thyroid dysfunction in children after the Fukushima Nuclear Disaster: an observational study.

PURPOSE: Stable iodine prophylaxis helps prevent childhood thyroid cancer in nuclear emergencies; however, there is limited information on its effect on thyroid function. This study aimed to examine thyroid function and autoimmunity among children and adolescents that took stable iodine after the Fukushima Nuclear Disaster. METHODS: For this observational study, data were obtained from children and adolescents that underwent thyroid cancer screening at Hirata Central Hospital from April 2012 to March 2018. Participant characteristics, including possible hypothyroidism and hyperthyroidism, were compared between the prophylaxis and no-prophylaxis groups. Multivariable logistic regression models were used to assess for possible hypothyroidism, autoantibodies positive, and hyperthyroidism. RESULTS: A total of 1,225 participants with stable iodine prophylaxis and 3,946 without prophylaxis were enrolled. Of those participants, blood samples were available for 144 and 1,201 participants in the prophylaxis and no-prophylaxis groups, respectively. There were 17 (11.8%) and 146 cases (12.2%) of possible hypothyroidism or autoantibodies positive cases in the prophylaxis and no-prophylaxis groups, respectively, and there were no cases and 3 cases (0.2%) of possible hyperthyroidism in those two groups, respectively. Multivariable analysis for possible hypothyroidism revealed no association between stable iodine intake and possible hypothyroidism or autoantibodies positive [odds ratio 0.716 (95% confidence interval 0.399-1.284)] (p = 0.262). We did not perform multivariable analysis for hyperthyroidism due to the limited number of cases. CONCLUSION: Significant adverse effects of stable iodine intake on thyroid function were not observed among children and adolescents 7 years after the Fukushima Nuclear Disaster.

Effect of tumor burden and growth rate on treatment outcomes of nivolumab in head and neck cancer.

BACKGROUND: Nivolumab improves overall survival (OS) in patients with platinum-refractory recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). In one study, however, Kaplan-Meier OS and progression-free survival (PFS) curves for the nivolumab and cytotoxic agent arms crossed at 3-6 months, suggesting that patients with initial resistance to immunotherapy might have better outcomes with cytotoxic treatment. Here, we explored the conditions and candidates which are predictive of nivolumab outcomes in R/M HNSCC. METHODS: We retrospectively reviewed the clinical records of 27 consecutive R/M HNSCC patients treated with nivolumab from 2014 to 2018. Tumor size was evaluated by RECIST ver.1.1. Tumor growth rate (Gr) was defined as 3log(D0/Dpre)/t, where D0 and Dpre are the sum of the diameters of the target lesions (SumTLs) at baseline and pre-baseline, and t is time, with 1t defined as 4 weeks. RESULTS: Twenty-five patients were enrolled. Survival was significantly worse in patients with disease progression within 3 months. Outcomes appeared poorer in patients with higher pre-treatment Gr and bigger SumTLs at baseline. We therefore explored the association between prognosis, Gr and SumTLs. Recursive partitioning analysis showed that the characteristics of patients with disease progression after 3 months were Gr < 0.76 and SumTLs < 31.0 mm. Further, Gr < 0.76 and SumTLs < 31.0 mm was associated with significantly longer PFS (p = 0.01) and OS (p < 0.01). CONCLUSIONS: These results suggest that Gr and SumTLs at baseline are significantly associated with OS and PFS in R/M HNSCC patients treated with nivolumab.

Isotope Effect on Energy Confinement Time and Thermal Transport in Neutral-Beam-Heated Stellarator-Heliotron Plasmas.

The isotope effect on energy confinement time and thermal transport has been investigated for plasmas confined by a stellarator-heliotron magnetic field. This is the first detailed assessment of an isotope effect in a stellarator heliotron. Hydrogen and deuterium plasmas heated by neutral beam injection on the Large Helical Device have exhibited no significant dependence on the isotope mass in thermal energy confinement time, which is not consistent with the simple gyro-Bohm model. A comparison of thermal diffusivity for dimensionally similar hydrogen and deuterium plasmas in terms of the gyroradius, collisionality, and thermal pressure has clearly shown robust confinement improvement in deuterium to compensate for the unfavorable mass dependence predicted by the gyro-Bohm model.

A case with good response to belimumab for lupus nephritis complicated by IgG4-related disease.

Immunoglobulin (Ig)G4-related disease (IgG4-RD) is an unusual complication of systemic lupus erythematosus (SLE). We report a case in which belimumab proved efficacious for not only SLE, but also IgG4-RD. A 58-year-old Japanese woman had suffered from photodermatosis and erythema on the limbs for 20 years. She presented in slight fever and fatigue since 2016. Laboratory data showed hypergammaglobulinemia, proteinuria and positive results for anti-nuclear antibody and anti-double-stranded DNA antibody. Furthermore, elevated levels of serum IgG4 were detected. Contrast-enhanced computed tomography disclosed multiple areas of poor enhancement in the kidneys. The patient was diagnosed with lupus nephritis and IgG4-RD from renal biopsy. Treatment was started with prednisolone at 40 mg/day and mycophenolate mofetil. Proteinuria and serological findings improved initially, but tapering the dose of glucocorticoid proved difficult. After treatment was started with belimumab, clinical symptoms and proteinuria resolved completely. The dose of glucocorticoid was successfully tapered and serum concentration of IgG4 fell further. This appears to represent the first report of a case in which both SLE and IgG4-RD were effectively treated using belimumab.

Preoperative CT-based predictive factors for resectability and medium-term overall survival in patients with peritoneal carcinomatosis from colorectal cancer.

AIM: To determine preoperative radiological findings that may correlate with resectability and medium-term overall survival (OS) in patients with peritoneal carcinomatosis (PC) from colorectal cancer (CRC). MATERIALS AND METHODS: The study included 81 consecutive patients with PC scheduled for cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). PCI scores from preoperative computed tomography (CT) were compared with Peritoneal Cancer Index (PCI) scores at laparotomy. Odds ratio (OR), a Cox proportional hazards regression model, and Kaplan-Meier survival analyses were performed to evaluate resectability ("open and close procedure" [O&C]) and OS. RESULTS: A radiological PCI score ≥20 (OR; 20.61 p=0.001), involvement of the perihepatic region (OR; 3.63, p=0.047) and extensive small bowel involvement (OR; 9.90, p=0.019) were risk factors for O&C. Involvement of the left abdominal region correlated adversely to OS (HR; 6.86, p<0.001). CONCLUSIONS: The location of PC, in addition to the extent of PC as determined by preoperative CT, predicts resectability and medium-term survival.

Effects of ingesting milk fermented by Lactococcus lactis H61 on skin health in young women: a randomized double-blind study.

We conducted a randomized double-blind trial to evaluate the effects of fermented milk produced using only Lactococcus lactis strain H61 as a starter bacterium (H61-fermented milk) on the general health and various skin properties of young women. Healthy female volunteers (n=23; age=19-21r) received H61-fermented milk (10(10) cfu of strain H61/d) or conventional yogurt (10(10) cfu of both Lactobacillus delbrueckii ssp. bulgaricus and Streptococcus thermophilus per day), as a reference food, daily for 4 wk. Before and at the end of 4 wk, blood samples were taken, and skin hydration (inner forearms and cheek) and melanin content, elasticity, and sebum content (cheek only) were measured. Skin hydration at the inner forearm was higher at wk 4 than at wk 0 in both groups. Sebum content in cheek rose significantly after intervention in the H61-fermented milk group, but not the conventional yogurt group. Other skin parameters did not differ in either group. Serum analysis showed that total protein concentration and platelet count were elevated and reactive oxygen species decreased in both groups after the intervention. Although H61-fermented milk and conventional yogurt had similar effects on skin status and some blood characteristics of participants, an increase of sebum content in cheek is preferable to H61-fermented milk. As skin lipids contribute to maintaining the skin barrier, H61-fermented milk would provide beneficial effects on skin for young women.

The initial change in tumor size predicts response and survival in patients with metastatic colorectal cancer treated with combination chemotherapy.

BACKGROUND: To determine whether the change in tumor diameters at the first follow-up computed tomography (CT) examination after baseline examination (first change) correlates with outcome in patients with metastatic colorectal cancer (mCRC) treated with combination chemotherapy. PATIENTS AND METHODS: The first change was analyzed in a multicenter randomized phase III trial (Nordic VI, N = 567) comparing first-line irinotecan with either bolus or infused 5-fluorouracil. Cox proportional hazards multiple regression model and Kaplan-Meier survival analyses after correction for guarantee-time bias were carried out to evaluate correlations between first change, objective response according to RECIST 1.0, progression-free survival (PFS), and overall survival (OS). RESULTS: The hazard ratios for PFS and OS decreased along with first change. A decrease between 10% and <30%, albeit RECIST does not regard this as a partial response, was a positive prognostic factor for PFS and OS. Patients who had new lesions or unequivocal progression of nonmeasurable lesions had a worse prognosis than those with only an increase in size of >20%. CONCLUSIONS: The change in tumor size at the first follow-up CT is strongly prognostic for PFS and OS in mCRC.

Commensal symbiosis between a Lactococcus lactis strain and an Enterococcus mundtii strain increases cell yield in constituted broth.

To exert their beneficial effects, probiotics need to survive in the stringent conditions of the gastrointestinal tract. Symbiosis between different bacteria is a potential way of enhancing this survival. In developing new probiotic cultures, we investigated the synergic effect between Enterococcus mundtii IFO 13712 and 7 strains of Lactococcus lactis, many of which are widely used as starter bacteria for making dairy products and have probiotic properties. The growth yield of a mixed culture of L. lactis strain Y and IFO 13712 in de Man, Rogosa, and Sharpe broth was greater than that of a single culture. Supernatant from culture of strain IFO 13712 enhanced the growth of strain Y, but that of strain Y did not enhance the growth of strain IFO 13712. This commensalism phenomenon was confirmed by using a simpler tryptone-yeast extract-glucose (TYG) broth. Increased cell yield in mixed culture of the 2 strains compared with single cultures was observed in TYG broth in the presence of both Tween 80 and citrate but not in TYG broth alone or TYG broth containing either Tween 80 or citrate. Thus, the Tween 80 and citrate in the broth contributed to the commensalism. Metabolite analysis revealed that ethanol production in the co-metabolism of glucose and citrate by strain Y was suppressed by mixed culture in TYG broth containing Tween 80 and citrate, compared with that in TYG broth containing citrate alone. The mechanism supporting the observed commensal symbiosis between strains Y and IFO 13712 was the increase in availability of glucose for lactate production by strain Y because, in glycolysis, the pathway from glucose to lactate is energic, whereas the pathway from glucose to ethanol is not. Whether growth stimulation of strain Y by mixing it with IFO 13712 in milk products will enhance the survival of strain Y in the intestine remains to be elucidated.

A derivative of Lactococcus lactis strain H61 with less interleukin-12 induction has a different cell wall.

Lactococcus lactis H61 can increase the cellular immune responses of aged (14-mo-old) senescence-accelerated mice. The aim of this study was to investigate the factors contributing to IL-12 induction by strain H61 by analyzing strains derived from it. Strain H61 derivative no. 13 was obtained by growing the parent strain at 37°C. This derivative induced significantly lower production of IL-12 from J774.1 macrophage cells than did the parent strain H61. The 2 strains differed in the resistance of their whole cells or cell walls to lysozyme, a cell wall-degrading enzyme. Sodium hydroxide treatment to de-O-acetylate muramic acid in the cell walls of the 2 strains reduced the lysozyme resistance, compared with untreated cell walls: at 3h after adding lysozyme, the lysozyme resistance of untreated and NaOH treated cell wall from strain H61 was 55.4% and 11.7%, respectively. The values of untreated and NaOH-treated cell walls from strain no.13 were 73.7 and 42.8%, respectively. The reduction was higher in strain H61, indicating that the cell walls of strain H61 were highly O-acetylated. Trichloroacetic acid treatment to remove wall-associated polymers such as teichoic acids made the lysozyme resistance of the cell walls of both strains similar. The sugar content of cell walls prepared from strain H61 was significantly higher than that of strain no. 13 cell wall. A derivative with less activity for inducing IL-12 by macrophage cells had less O-acetylation and had lower sugar content in the cell wall than did strain H61. Modifying the cell wall of strain H61 may be a useful way to regulate its ability to induce IL-12. Strain H61 has been used as a starter bacterium in the dairy industry. This study could lead to enhancing the value of dairy products made by strain H61 by characterizing the key factor(s) responsible for its stimulation of immunity.

Interaction between Lactococcus lactis and Lactococcus raffinolactis during growth in milk: development of a new starter culture.

Many milk fermentations use mixed cultures of lactic acid bacteria. To select a new mixed starter culture, 100 acid-producing bacterial strains were isolated from raw cow milk. Of these, 13 strains identified as belonging to the genera Lactococcus, Lactobacillus, Leuconostoc, or Weissella (based on phenotypic and genotypic tests) were assessed for a symbiotic effect between pairs of isolated strains during growth in milk. Among the strains tested, a mixed culture of Lactococcus lactis ssp. lactis strain 54 and Lactococcus raffinolactis strain 37 stimulated greater acid production during fermentation than occurred with pure fermentation. This stimulatory effect was not observed in milk supplemented with yeast extract or glucose or in constituted medium. Addition of a cell-free filtrate from milk fermented by strain 54 increased acid production by strain 37; however, the converse effect was not observed. The increased acid production by this mixed culture was, therefore, due to stimulation of strain 37 by metabolic products of strain 54, suggesting that the interaction between strains 54 and 37 is commensal. Analysis with a taste-sensing system indicated that fermented milk containing the mixed culture was more acidic, had more anionic bitterness, had greater aftertastes of anionic bitterness and astringency, and was less salty and umami than milk containing the individual cultures. This study identifies a new commensal relationship between 2 lactococcal strains that are commonly used for making dairy products.

Prevention of excessive collagen accumulation by human intravenous immunoglobulin treatment in a murine model of bleomycin-induced scleroderma.

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrotic changes in skin and other organs involving excessive collagen deposition. Here we investigated the effect of intravenous immunoglobulin (IVIG) on fibrosis in a murine model of bleomycin (BLM)-induced scleroderma. Scleroderma was induced in C3H/He J mice by subcutaneous BLM injections daily for 35 days. The collagen content in skin samples from the BLM-injected group (6·30 ± 0·11 mg/g tissue) was significantly higher than the PBS group (5·80 ± 0·10 mg/g tissue), and corresponded with dermal thickening at the injection site. In contrast, mice treated with IVIG for 5 consecutive days after initiating BLM injection showed lesser collagen content significantly (IVIG group, 5·61 ± 0·09 mg/g tissue; BLM vs. IVIG). In order to investigate the cellular and protein characteristics in the early stage of the model, the skin samples were obtained 7 days after the onset of experiment. Macrophage infiltration to the dermis, monocyte chemoattractant protein (MCP-1)-positive cells, and increased TGF-ß1 mRNA expression were also observed in the BLM group. IVIG inhibited these early fibrogenic changes; MCP-1 expression was significantly lesser for the IVIG group (1·52 ± 0·19 pg/mg tissue) than for the BLM group (2·49 ± 0·26 pg/mg tissue). In contrast, TGF-ß1 mRNA expression was significantly inhibited by IVIG. These results suggest that IVIG treatment may inhibit macrophage recruitment to fibrotic sites by down regulating MCP-1 and TGF-ß production, and thus could be a potential drug for managing fibrotic disorders such as SSc.

Lactococcus strains treated with heat and hen-egg-white lysozyme induce abundant interleukin-12 production by J774.1 macrophages and murine spleen cells.

The IL-12-inducing ability of lactic acid bacteria could be a critical index of immunomodulatory activity, especially in promoting T-helper-1 responses and in suppressing T-helper-2-mediated allergic responses. We aimed to develop a simple method for enhancing the IL-12-inducing ability of bacteria. We examined the in vitro effects of strains of lysozyme-modified Lactococcus (ML-LYS), prepared by heat treatment of the Lactococcus strain in the presence of lysozyme, on the ability of mouse macrophage-like J774.1 cells and spleen cells to produce IL-12. An IL-12-inducing ability greater than that of heat-killed bacteria was shown by 41 of 46 ML-LYS strains in J774.1 cells and by all 46 ML-LYS strains in mouse spleen cells. In contrast, bacteria modified by α-lactalbumin, ß-lactoglobulin, or ovalbumin did not enhance IL-12 production in J774.1 cells. Microscopically, ML-LYS showed stronger resistance to lysozyme and macrophage digestion than did heat-killed bacteria or the other modified bacteria. Addition of chitotriose, a lysozyme inhibitor, enhanced IL-12 production by J774.1 cells stimulated with heat-killed bacteria. Therefore, enhancement of resistance to lysozyme may be a key factor in the strong IL-12-inducing ability of ML-LYS. These findings have important implications for the design of dairy products that have an immunomodulatory effect using the modified bacteria.

Analysis of the Motional Stark Effect (MSE) diagnostic to measure the rotational transform and current profile in the Large Helical Device.

The analysis method of the Motional Stark Effect (MSE) diagnostic to measure the rotational transform and current profiles in the Large Helical Device has been improved. This was done by using the Variational Moments Equilibrium Code to calculate an equilibrium database for various pressure profiles and current profiles. This method looks for the radial profile of the rotational transform in the equilibrium database that gives the best fit to the polarization angle profiles measured with the MSE diagnostic. This analysis improves the measurements of rotational transform, especially near the magnetic axis, where the sensitivity of the polarization angle measurements becomes low and the uncertainty due to error in the estimation of the Pfirsch-Schlüter current becomes large. The radial profiles of the rotational transform and current profiles for Electron Cyclotron Current Drive and Neutral Beam Current Drive are obtained in the new analysis method with a sufficiently high accuracy to discuss the discrepancy of the current density profiles between the measurements and the calculations.

A new multi-tracer pellet injection for a simultaneous study of low- and mid/high-Z impurities in high-temperature plasmas.

A new multi-tracer technique in the Tracer-Encapsulated Solid Pellet (TESPEL) method has been developed in order to acquire simultaneously the information about the behaviors of various impurities, i.e., to study concurrently the behaviors of low- and mid/high-Z impurities in magnetically confined high-temperature plasmas. In this new technique, an inorganic compound (for example, lithium titanate, Li2TiO3) is proposed to be used as a tracer embedded in the core of the TESPEL, instead of pure elements. The results of the proof-of-principle experiment clearly demonstrate the applicability of the new multi-tracer technique in the TESPEL method for the simultaneous study of behaviors of low- and mid/high-Z impurities in high-temperature plasmas.

Sequence analysis of a pea comb locus on chicken chromosome 1.

To facilitate gene identification, this study aimed to narrow the scope of the genome region affecting chicken comb type by using two bird populations. First, an F2 resource population was generated by crossing Japanese game fowl (Shamo; pea comb, P/p and P/P) with White Plymouth Rock (single comb, p/p). Comb types of the 240 F2 offspring produced by an F1 intercross between eight males and 57 females were segregated at a ratio of 3:1 (pea:single). The pea comb locus was mapped to a chromosomal region on Gallus gallus chromosome 1 that was flanked by microsatellite markers MCW0112, MCW0019 and ABR521. The second population (five-generation, n=1300 animals) was derived from a cross between Shamo and Rhode Island Red (single comb, p/p) that had been genotyped for additional polymorphic single nucleotide polymorphisms and microsatellite markers within this region through development of chicken draft sequences. To close some gaps in these draft sequences, we constructed a bacterial artificial chromosome contig and sequenced it using the shotgun sequencing technique. Chickens selected from pedigrees in these populations were grouped by inheritance of a P or p haplotype at the locus constructed by the additional markers. Finally, this locus was fine-mapped to roughly 60 kb based on the association of haplotypes and comb types. Chicken genome sequences suggest that the most likely polymorphism responsible for the pea comb locus is a duplicated sequence and that the sex determining region Y-box 5 gene, one predicted gene and one expressed sequence tag in a critical region may be associated with the duplicated sequence.

Automated diagnosis of intestinal parasites: A new hybrid approach and its benefits.

Intestinal parasites are responsible for several diseases in human beings. In order to eliminate the error-prone visual analysis of optical microscopy slides, we have investigated automated, fast, and low-cost systems for the diagnosis of human intestinal parasites. In this work, we present a hybrid approach that combines the opinion of two decision-making systems with complementary properties: (DS1) a simpler system based on very fast handcrafted image feature extraction and support vector machine classification and (DS2) a more complex system based on a deep neural network, Vgg-16, for image feature extraction and classification. DS1 is much faster than DS2, but it is less accurate than DS2. Fortunately, the errors of DS1 are not the same of DS2. During training, we use a validation set to learn the probabilities of misclassification by DS1 on each class based on its confidence values. When DS1 quickly classifies all images from a microscopy slide, the method selects a number of images with higher chances of misclassification for characterization and reclassification by DS2. Our hybrid system can improve the overall effectiveness without compromising efficiency, being suitable for the clinical routine - a strategy that might be suitable for other real applications. As demonstrated on large datasets, the proposed system can achieve, on average, 94.9%, 87.8%, and 92.5% of Cohen's Kappa on helminth eggs, helminth larvae, and protozoa cysts, respectively.

Pre-Golgi degradation of newly synthesized T-cell antigen receptor chains: intrinsic sensitivity and the role of subunit assembly.

The T cell antigen receptor (TCR) is a multisubunit complex composed of at least seven transmembrane chains. The predominant species in most T cells has the composition alpha beta gamma delta epsilon zeta 2. The roles of subunit assembly in transport out of the ER and in the recently described process of pre-Golgi degradation of newly synthesized TCR chains were analyzed in a T-cell line deficient in the synthesis of delta chains (delta 2) and in COS-1 fibroblasts transfected with genes encoding individual TCR chains. Studies with the delta-deficient T-cell line showed that, in the absence of delta, the other TCR chains were synthesized at normal rates, but, instead of being transported to the cell surface, they were retained in the ER. Analysis of the fate of TCR chains retained in the ER showed that they were degraded at vastly different rates by a nonlysosomal pathway. Whereas the alpha chains were degraded rapidly, gamma, zeta, and epsilon were relatively long-lived. To analyze whether this selective degradation was because of different intrinsic susceptibility of the individual chains to degradation or to the formation of resistant oligomers, TCR chains were expressed alone or in combinations in COS-1 fibroblasts. These studies showed that (a) individual TCR chains were degraded at different rates when expressed alone in COS-1 cells, and (b) sensitive chains could be stabilized by coexpression with a resistant chain. Taken together, these observations indicate that both intrinsic sensitivity and subunit assembly play a role in determining the rates at which newly synthesized TCR chains are degraded in the ER.